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Background In the recent years, an increased use of marginal donors and grafts and a growing prevalence of peripheral arterial disease in the recipients have been observed. Meanwhile, the open surgical technique for kidney transplantation has not changed. The aim of this study is to analyze all surgical complications occurring in the first year after kidney transplant and to determine potential predictive risk factors. Method Data of the 399 patients who underwent kidney transplant in our University Hospital between January 2006 and December 2015 were retrospectively reviewed. The primary endpoint was the overall rate of vascular, parietal and urological complications at 1 year following kidney transplantation. The secondary outcomes were graft and patient’ survival rates, and the identification of predictive factors of the surgical complications. Results Twenty-four percent of patients developed 134 complications. Vascular complication represented 39% of all complications and resulted in 9 graft losses. Parietal and urological complications represented 46% and 15% of all complications, respectively, No parietal or urological complications were associated with graft loss. Five patients died during the first year, none of these cases was associated with graft loss. The graft survival rate reached 96% at 1 year, including patients still alive. The occurrence of surgical complication was associated with reduced graft survival at 1 year. Using a multivariate analysis, 4 predictive factors were identified: age, deceased donor, operative time and dyslipidemia. Conclusion Surgical complications after kidney transplantation remained frequent and age, deceased kidney donors, and operative time were identified as risk factors. As vascular complications were a major cause of early graft loss, efforts should aim to reduce their occurrence to increase graft survival.

Incisional hernias (IH) constitute a complication after kidney transplant (KT). Patients may be particularly at risk because of comorbidities and immunosuppression. The study aim was to assess the incidence, risk factors, and treatment of IH in patients undergoing KT. This retrospective cohort study included consecutive patients who underwent KT between January 1998 and December 2018. Patient demographics, comorbidities, perioperative parameters, and IH repair characteristics were assessed. Postoperative outcomes included morbidity, mortality, need for reoperation, and length of stay (LOS). Patients who developed IH were compared with those who did not develop one. Forty-seven patients (6.4%) developed an IH after a median delay of 14 months (IQR, 6-52 months) in 737 KTs. On uni- and multivariate analyses, body mass index (odds ratio [OR], 1.080; P = .020), pulmonary diseases (OR, 2.415; P = .012), postoperative lymphoceles (OR, 2.362; P = .018), and LOS (OR, 1.013; P = .044) were independent risk factors. Thirty-eight patients (81%) underwent operative IH repair, and 37 (97%) were treated with a mesh. The median LOS was 8 days (IQR, 6-11 days). Three patients (8%) developed surgical site infections, and 2 patients (5%) presented hematomas requiring surgical revision. After IH repair, 3 patients (8%) had a recurrence. The incidence of IH after KT seems rather low. Overweight, pulmonary comorbidities, lymphoceles, and LOS were identified as independent risk factors. Strategies focusing on the modifiable patient-related risk factors and early detection and treatment of lymphoceles may help to decrease the risk of IH formation after KT.

BackgroundThere is no consensus on how to predict post-transplant function of donation after circulatory death (DCD) kidneys. Thus, we aimed to identify renal scintigraphy parameters that could predict 1-year kidney function.MethodsIn this single center study, we included all consecutive DCD kidney recipients between 2013 and 2021 (n = 29). Patients who did not have a scintigraphy within 10 days of transplantation (n = 3), recipients of multiple organs and less than 18 years old were excluded (n = 1). Primary endpoint was the estimated glomerular filtration rate (eGFR).ResultsMedian eGFR and serum creatinine at 1 year were 67 µmol/L (56–81) and 111 ml/min (99–132), respectively. Among parameters tested, the 3rd/2nd-minute activity ratio had the best diagnostic performance (AUC: 0.74 and 0.71, for eGFR and creatinine) 1 year post transplantation. Using 1.21 as the best cut off, the 3rd/2nd-minute activity ratio specificity and sensitivity to predict eGFR >60 ml/min was 0.82 and 0.83. Renal function was significantly better at 1 week, 3, 6, and 12 months after transplantation in patients with 3rd/2nd-minute activity ratios above 1.21.ConclusionThis study suggests that the 3rd/2nd-minute activity ratio can predict graft function at 1 year. The benefit of post-transplant scintigraphy should be further validated in a prospective cohort.

Fluid overload has been associated with a high prevalence of sleep apnea (SA) in patients with end-stage kidney disease (ESKD). In this prospective study, we hypothesized that improvement in kidney function and hydration status after kidney transplantation (Tx) may result in an improvement in SA severity. A total of 196 patients on the kidney Tx waiting list were screened for SA using home nocturnal polysomnography (PSG) to measure the apnea-hypopnea index (AHI) and underwent bioimpedance to assess body composition. Of 88 participants (44.9%) with SA (AHI ≥ 15/h), 42 were reassessed 6 months post-Tx and were compared with 27 control patients. There was a significant, but small, post-Tx improvement in AHI (from 44.2 ± 24.3 to 34.7 ± 20.9/h, P = .02) that significantly correlated with a reduction in fluid overload (from 1.8 ± 2.0 to 1.2 ± 1.2 L, P = .02) and body water (from 54.9% to 51.6%, P = .003). A post-Tx increase in body fat mass (from 26% to 30%, P = .003) possibly blunted the beneficial impact of kidney Tx on SA. All parameters remained unchanged in the control group. In conclusion, SA is a frequent condition in ESKD patients and partially improved by kidney Tx. We suggest that SA should be systematically assessed before and after kidney Tx. ClinicalTrials.gov Identifier: NCT02020642.

International audience; No abstract available

Improved glycemic control with a bionic pancreas and recent safety data of a wearable artificial pancreas may be relevant for kidney transplant recipients with type 1 diabetes [1, 2]. Diabetes is a major risk factor for end-stage renal disease, and the DCCT trial showed that tight glycemic control is superior to conventional insulin therapy to prevent complications of type 1 diabetes, including diabetic nephropathy [3]. Moreover, continuous subcutaneous insulin pump infusion partially prevented early diabetic nephropathy in native kidneys in another 3-year follow-up study which included kidney biopsies [4]. In kidney allografts, the risk of recurrent biopsy-proven diabetic nephropathy is almost 100 % after 10 years of follow-up, and histological diabetic lesions can be observed as soon as 2 years after transplant [5]. Kidney– pancreas transplantation with its associated euglycemia can prevent recurrent diabetic nephropathy in the allograft [6, 7]. However, kidney–pancreas transplantation is associated with significant morbidity, and donor organ shortage limits its widespread application [8]. Islet after kidney transplantation can also potentially reduce long-term diabetic complications; however, the rate of insulin independence after islet transplantation remains significantly lower as compared to full pancreas transplantation [9].

MELD exceptions are designed to equipoise liver transplant waiting list survival. We aimed to analyze the impact of the MELD Upgrade rule and all other MELD exceptions on the liver transplant waiting list outcomes during 2012-2017 in Switzerland.We conducted a nationwide cohort study including all adult patients registered on the Swiss liver transplant waiting list between 2012 and 2017. Waiting list mortality and access to transplantation were analyzed, considering MELD exceptions as time-dependent covariates.730 patients were included. Patients with MELD Upgrade exceptions had a higher risk of dying while on the waiting list (OR 2.13; CI 95% 1.30-3.47) and also an increased likelihood of receiving a liver transplantation, when compared to patients without MELD exceptions. Patients with any type of MELD exceptions were more likely to be transplanted when compared to patients without MELD exceptions. The proportion of patients with MELD exceptions increased from 2012 to 2017 (44% vs 88%). Allocation MELD at the time of transplantation showed an annual increase (23 ± 8 points vs 32 ± 5 points, p 0.001).Only patients with MELD Upgrade exceptions had the expected combination of higher waiting list mortality and quicker access to liver transplantation.

Titre Variations et anomalies nephrologiques, vasculaires et urologiques chez les candidats au don vivant renal. Introduction Cette etude consiste a determiner I.a prevalence des variations anatomiques (renales, vasculaires et urologiques) ainsi que des pathologies renales acquises dans une population de candidats au don vivant de rein (CDVR). Materiel et methodes Il s'agit d'une etude retrospective de tous les CDVR referes dans notre centre en vue d'une transplantation renale entre avril 2003 et se pt embre· 2014. Sur les 491 CDVR, 189 ont ete initialement exclus pour des raisons medicales (n=140) ou autres (n=49), sans avoir effectue de bilan radiologique. 302 ont beneficie d'un bilan radiologique (angio-CT ou IRM) en prevision du don et 226/302 (73.5%) ont pu donner un rein. Resultats Une ou plusieurs variations anatomiques et/ou anomalies acquises ont ete constatees chez 178/302 (58.9%) des CDVR, dont les plus frequentes concernaient les anomalies et variations arterielles (arteres multiples, fibrodysplasie, anevrisme, stenose 70%), presentes chez . 39.3% des CDVR, suivies par les variations veineuses (27.8%). Des calculs ont ete observes chez 5.6% des C:DVR et les anomalies des voies urinaires (duplicite/bifidite ureterale) ont concerne 3.0% des CDVR. Aucune tumeur maligne n'a ete diagnostiquee alors que 4 tumeurs benignes (1.3%) ont ete identifiees, dont un cas necessitant des investigations supplementaires. Conclusion Nous constatons une haute prevalence de variations anatomiques et anomalies acquises dans une population de CDVR. Cependant, ces variantes et anomalies constatees ont conduit a exclure seulement 4 % des candidats. Ceci soit parce que les anomalies ne contre­ indiquaient pas le prelevement, soit parce que dans la majorite des cas le. rein controlateral a pu etre utilise.

Background: Data on individualized immunosuppressive protocols for the pediatric heart recipients are missing in Europe. To contribute to this very small but specialized field, we describe the use of induction therapy (IT) in pediatric heart transplant patients in Switzerland and the retrospective outcomes. Method: This is a retrospective national database analysis of children

Transplantation has become a valid therapeutic option for an increasing number of patients with end-stage organ disease. The emergence of SARS-CoV-2 coronavirus infection and associated disease (COVID-19) has alarmed the transplant community, since recommendations for adequate follow-up of organ transplant recipients during the acute phase of a pandemic are limited. Furthermore, treatment options against COVID-19 disease and adequate adjustment of immunosuppression in at risk patients remain a concern. This review summarizes current knowledge on the incidence and clinical course of SARS-CoV-2 infection in patients with solid organ transplantation. It also discusses therapeutic strategies and provides general recommendations on how to proceed with transplantation programs in a time when health care resources may become scarce.La transplantation d’organes permet de prolonger et d’améliorer la qualité de vie d’un nombre croissant de patients. Dans le contexte de la pandémie actuelle de l’infection au coronavirus SARS-CoV-2 et de la maladie qui en découle (COVID-19), la communauté de transplantation s’interroge sur le risque encouru par les patients greffés, sur la manière d’assurer un suivi adéquat d’une population à risque, et sur le schéma thérapeutique à adopter en cas de maladie avérée. Dans cet article nous décrivons les connaissances actuelles quant à l’incidence et à l’évolution de l’infection SARS-CoV-2 chez des patients greffés. En accord avec les sociétés de discipline, nous proposons des recommandations de prise en charge thérapeutique, et amenons quelques éléments de réflexion en tenant compte d’une possible limitation des ressources et d’une situation pandémique évolutive.

Introduction et but de l'etude Le traitement de choix lors d'insuffisance renale terminale est la transplantation. Malgre un faible taux de complications operatoires, des perturbations hemodynamiques peuvent evoquer une perte de greffon. Les principales complications vasculaires sont des erreurs techniques ou un mauvais positionnement du rein ou de ses vaisseaux, pouvant mener a une perte du greffon, dramatique d'autant plus lors de transplantation a donneur vivant. Le benefice de l'echographie precoce a la recherche de problemes vasculaires a deja ete demontre, mais son role en intra- operatoire reste peu clair. Le but de cette etude etait d'evaluer d'eventuelles differences de complications post-operatoires avec et sans utilisation systematique de l'ultrasonographie Doppler per-operatoire, lors de transplantation renale a donneur vivant. L'objectif secondaire etait d'etablir une valeur seuil ou un index de resistance predictif, motivant une reprise chirurgicale. Materiel et methode Sur une periode de 10 ans, 108 greffes renales consecutives ont ete realisees a partir de donneurs vivants dans notre etablissement. Deux groupes ont ete crees selon l'utilisation ou non de l'echographie per- operatoire. Dans le groupe 1 (n=67), une echographie Doppler a ete systematiquement realisee avec mesure de l'indice de resistance intra- parenchymateux, alors que dans le groupe 2 (n=41), aucune echographie n'a ete realisee. Dans le groupe 1, nous avons recherche les donnees de l'echographie intra-operatoire, les index de resistance et les eventuelles modifications chirurgicales immediates. Le taux de complications vasculaires et non-vasculaires, de re-operations et de rejets aigus ont ete compares dans les deux groupes. Resultats Nos analyses ne montrent pas de differences sur le taux de complications postoperatoires globales, ni la survie du greffon ou du patient entre les deux groupes. Cependant, le taux de complications vasculaires (10% vs 0%, p = 0,02) est significativement plus eleve dans le groupe 2. Le taux de rejets aigus est egalement plus eleve (37% vs 10%) dans le groupe 2. Nous proposons une valeur seuil pour l'index de resistance inferieur a 0,5 pour justifier une revision chirurgicale immediate. Conclusion Cette etude est le premier rapport demontrant les avantages de l'echographie Doppler intra-operatoire systematique sur les complications postoperatoires dans la transplantation renale a donneurs vivants. D'apres nos resultats, une revision chirurgicale est recommandee lors d'index de resistance inferieur a 0,5.

To evaluate outcomes and post-donation kidney function of older living kidney donors (LKD). Retrospective analysis of prospective database including all consecutive LKD undergoing laparoscopic nephrectomy in a single center (09/1998-12/2013). LKD aged ≥60 years were compared to younger LKD. Renal function assessed by creatinine levels and estimated glomerular filtration rates (eGFR). Surgical complications classified according to the Clavien-Dindo classification. Bivariate and multivariate analyses using linear mixed effect models were performed to determine factors (age, gender, hypertension status, BMI, choice of better functioning kidney for donation) that might impinge on renal function after donation. 213 LKD were identified: 49 older (median age: 66 years, range: 60-79) and 164 younger (median age: 46, range: 25-59). Mean operative time (149 vs. 152 min, p = 0.69), conversion to laparotomy (n = 1 vs. 3, p = 0.92), grade III-IV complications (n = 4 vs. 2, p = 0.36) were similar. Older had more grade I-II complications (n = 18 vs. 4, p < 0.001). Despite similar pre-donation eGFR (80 vs. 84 ml/min/1.73 m 2 ), older donors presented significantly lower eGFR during inpatient period (46 vs. 51 ml/min/1.73 m 2 , p = 0.0003), at 1 month (51 vs. 58 ml/min/1.73 m 2 , p = 0.002) and at 1 year (54 vs. 62 ml/min/1.73 m 2 , p = 0.001). Multivariate analysis adjusted to gender, hypertension status, BMI and choice of better functioning kidney for donation showed that at 1 year, age ≥60 affected renal function by a coefficient of 0.91 (p < 0.001). Despite renal function improvement after discharge, LKD ≥ 60 years presented lower eGFR than younger at one year and had more grade I-II surgical complications.

Alagille syndrome is a rare disorder with low physician awareness. It affects multiple organs and thus patient management involves several medical specialties. It is an autosomal dominant disorder with significant intrafamilial variability. The most frequent clinical manifestations are neonatal jaundice, chronic cholestasis as well as cardiac, ocular and skeletal malformations associated with characteristic facial features. Inherited mutations affect the Notch pathway. Although the molecular basis of Alagille syndrome is well defined, no specific targeted therapy exists.Le syndrome d’Alagille est une pathologie rare et peu connue dans la pratique médicale. Il s’agit d’une affection multisystémique dont la prise en charge implique plusieurs spécialités médicales. Sa transmission se fait sur un mode autosomique dominant avec néanmoins une expression clinique très variable, au sein d’une même famille chez des sujets présentant une même mutation. Ses manifestations cliniques principales sont un ictère néonatal, une cholestase chronique, une atteinte cardiaque, oculaire, squelettique ainsi qu’un faciès caractéristique. Les diverses mutations identifiées et héritées affectent la voie de signalisation Notch. Bien que la physiopathologie soit actuellement relativement bien définie, aucune thérapie ciblée n’est à l’heure actuelle disponible.

Pretransplant anti-HLA donor-specific antibodies (DSA) are recognized as a risk factor for acute antibody-mediated rejection (AMR) in kidney transplantation. The predictive value of C4d-fixing capability by DSA or of IgG DSA subclasses for acute AMR in the pretransplant setting has been recently studied. In addition DSA strength assessed by mean fluorescence intensity (MFI) may improve risk stratification. We aimed to analyze the relevance of preformed DSA and of DSA MFI values.280 consecutive patients with negative complement-dependent cytotoxicity crossmatches received a kidney transplant between 01/2008 and 03/2014. Sera were screened for the presence of DSA with a solid-phase assays on a Luminex flow analyzer, and the results were correlated with biopsy-proven acute AMR in the first year and survival.Pretransplant anti-HLA antibodies were present in 72 patients (25.7%) and 24 (8.6%) had DSA. There were 46 (16.4%) acute rejection episodes, 32 (11.4%) being cellular and 14 (5.0%) AMR. The incidence of acute AMR was higher in patients with pretransplant DSA (41.7%) than in those without (1.6%) (p0.001). The median cumulative MFI (cMFI) of the group DSA+/AMR+ was 5680 vs 2208 in DSA+/AMR- (p=0.058). With univariate logistic regression a threshold value of 5280 cMFI was predictive for acute AMR. DSA cMFI's ability to predict AMR was also explored by ROC analysis. AUC was 0.728 and the best threshold was a cMFI of 4340. Importantly pretransplant DSA5280 cMFI had a detrimental effect on 5-year graft survival.Preformed DSA cMFI values were clinically-relevant for the prediction of acute AMR and graft survival in kidney transplantation. A threshold of 4300-5300 cMFI was a significant outcome predictor.

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of CRTC2 polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (PcorrectedA was significantly associated with several metabolic abnormalities. CRTC2 rs8450G>A appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.The Pharmacogenomics Journal advance online publication, 8 December 2015; doi:10.1038/tpj.2015.82.

Chronic active antibody-mediated rejection (caAMR) is a major cause of allograft loss after kidney transplantation (1). The BANFF 2013 classification redefined caAMR by the presence of donor-specific anti-HLA antibodies (DSA) together with immuno-histopathological evidence for active vascular lesions of the endothelium (C4d deposits, glomerulitis, peritubular capillaritis) as well as evidence of chronic tissue injury (transplant glomerulopathy, peritubular capillary basement membrane multilayering or arterial intimal fibrosis) (2,3). Humoral immunity, detected by the presence of DSA, and B cells are considered pivotal in the development of caAMR. Gosset et al. showed that circulating DSA are responsible for accelerated allograft fibrosis independently of acute AMR (1). This article is protected by copyright. All rights reserved.

New-onset diabetes mellitus after transplantation (NODAT) is a complication following solid organ transplantation (SOT) and may be related to immune or inflammatory responses. We investigated whether single nucleotide polymorphisms (SNPs) within 158 immune- or inflammation-related genes contribute to NODAT in SOT recipients. The association between 263 SNPs and NODAT was investigated in a discovery sample of SOT recipients from the Swiss Transplant Cohort Study (STCS, n 1 = 696). Positive results were tested in a first STCS replication sample (n 2 = 489) and SNPs remaining significant after multiple test corrections were tested in a second SOT replication sample (n 3 = 156). Associations with diabetic traits were further tested in several large general population-based samples (n > 480 000). Only SP110 rs2114592C>T remained associated with NODAT in the STCS replication sample. Carriers of rs2114592-TT had 9.9 times (95% confidence interval [CI]: 3.22-30.5, P = .00006) higher risk for NODAT in the combined STCS samples (n = 1184). rs2114592C>T was further associated with NODAT in the second SOT sample (odds ratio: 4.8, 95% CI: 1.55-14.6, P = .006). On the other hand, SP110 rs2114592C>T was not associated with diabetic traits in population-based samples, suggesting a specific gene-environment interaction, possibly due to the use of specific medications (ie, immunosuppressants) in transplant patients and/or to the illness that may unmask the gene effect.

Objectives To determine whether valganciclovir 450 mg every 48 h for cytomegalovirus (CMV) prophylaxis provides appropriate ganciclovir exposure in solid organ transplant recipients during continuous renal replacement therapy (CRRT). Patients and methods Ganciclovir pharmacokinetics was intensively studied in two lung transplant recipients under valganciclovir 450 mg every 48 h over one dosing interval. In vitro experiments using blank whole blood spiked with ganciclovir further investigated exchanges between plasma and erythrocytes. Results Ganciclovir disposition was characterized by apparent total body clearance of 3.3 and 5.8 L/h, terminal half-life of 16.9 and 14.1 h, and apparent volume of distribution of 60.3 and 104.9 L in Patients 1 and 2, respectively. The observed sieving coefficient was 1.05 and 0.96, and the haemofiltration clearance was 3.3 and 3.1 L/h. In vitro experiments confirmed rapid efflux of ganciclovir from red blood cells into plasma, increasing the apparent efficacy of haemofiltration. Conclusions A valganciclovir dosage of 450 mg every 48 h appears adequate for patients under CRRT requiring prophylaxis for CMV infection, providing concentration levels in the range reported for 900 mg once daily dosing outside renal failure.

Summary Annual influenza vaccination is recommended in solid organ transplant (SOT) recipients. However, concerns have been raised about the impact of vaccination on antigraft alloimmunity. We evaluated the humoral alloimmune responses to influenza vaccination in a cohort of SOT recipients between October 2008 and December 2011. Anti-HLA antibodies were measured before and 4–8 weeks after influenza vaccination using a solid-phase assay. Overall, 169 SOT recipients were included (kidney = 136, lung = 26, liver = 3, and combined = 4). Five (2.9%) of 169 patients developed de novo anti-HLA antibodies after vaccination, including one patient who developed donor-specific antibodies (DSA) 8 months after vaccination. In patients with pre-existing anti-HLA antibodies, median MFI was not significantly different before and after vaccination (P = 0.73 for class I and P = 0.20 for class II anti-HLA antibodies) and no development of de novo DSA was observed. Five episodes of rejection (2.9%) were observed within 12 months after vaccination, and only one patient had de novo anti-HLA antibodies. The incidence of development of anti-HLA antibodies after influenza vaccination in our cohort of SOT recipients was very low. Our findings indicate that influenza vaccination is safe and does not trigger humoral alloimmune responses in SOT recipients.

Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT) recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20) might have lower medication adherence than noncomplex patients (INTERMED≤20). Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20). Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11) and noncomplex patients (N=21) were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value). Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly morbid patients who have complex social and psychological characteristics.

BACKGROUND We assessed the impact of a preemptive strategy after discontinuation of antiviral prophylaxis in the prevention of late-onset cytomegalovirus (CMV) disease in a cohort of kidney transplant recipients. METHODS Patients undergoing kidney transplantation at the University Hospital of Lausanne (CHUV) between November 2003 and November 2007 were included if they were donor or recipient (D/R) seropositive for CMV. All patients received 3 months of prophylaxis with valganciclovir, followed by monitoring of CMV DNAemia by polymerase chain reaction (PCR) every 15 days during 3 additional months. Valganciclovir was restarted if CMV PCR was more than or equal to 10,000 copies/mL. The primary endpoint of the study was the incidence of late-onset CMV disease. RESULTS.: Eighty-six kidney transplant recipients were included; 30 patients were D+/R- and 56 patients were R+ for CMV. At 6 months posttransplant, CMV DNAemia had occurred in 31 of 86 (36%) patients: 13 of 30 (43%) in the D+/R- group and 18 of 56 (32%) in the R+ group (P = 0.35). In the D+/R- group, among the 13 patients with CMV DNAemia, 7 (54%) patients developed late-onset CMV disease, simultaneously to the first positive viral load (n = 5) or after detection of low-grade viremia (n = 2). Only two patients received a preemptive treatment. In the R+ group, all positive PCR results were below the established cutoff. Thus, these 18 patients were not treated, and none of them developed late-onset CMV disease (R+ vs. D+/R-: P < 0.001). CONCLUSIONS Within the limitations of a noncontrolled study, our data indicate that a preemptive strategy after 3 months of valganciclovir prophylaxis for CMV is not useful in R+ kidney transplant recipients. In D+/R- patients, this approach should be further evaluated.

Background. Few data are available regarding the immunogenicity and safety of the pandemic influenza vaccine in immunocompromised patients. We evaluated the humoral response to the influenza A H1N1/09 vaccine in solid-organ transplant (SOT) recipients, in patients with human immunodeficiency virus (HIV) infection, and in healthy individuals. Methods. Patients scheduled to receive the pandemic influenza vaccine were invited to participate. All participants received the influenza A H1N1/09 AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin. SOT recipients and HIV-infected patients received 2 doses at 3-week intervals, whereas control subjects received 1 dose. Blood samples were taken at day 0, day 21, and day 49 after vaccination. Antibody responses were measured with the hemagglutination inhibition assay (HIA) and a microneutralization assay. Results. Twenty-nine SOT recipients, 30 HIV-infected patients, and 30 healthy individuals were included in the study. Seroconversion measured by HIA was observed in 15 (52%) of 29 SOT recipients both at day 21 and day 49; in 23 (77%) of 30 at day 21 and 26 (87%) of 30 at day 49 in HIV-infected patients, and in 20 (67%) of 30 at day 21 and in 23 (77%) of 30 at day 49 in control subjects (P = .12 at day 21 and P = .009 at day 49, between groups). Geometric means of antibody titers were not significantly different between groups at day 21 or at day 49. Conclusions. Influenza A H1N1/09 vaccine elicited a similar antibody response in HIV-infected individuals and in control subjects, whereas SOT recipients had an overall lower response. A second dose of the vaccine only moderately improved vaccine immunogenicity in HIV-infected patients.

Since new technologies based on solid phase assays (SPA) have been routinely incorporated in the transplant immunology laboratory, the presence of pretransplantation donor-specific antibodies (DSA) against human leukocyte antigen (HLA) molecules has generally been considered as a risk factor for acute rejection (AR) and, in particular, for acute humoral rejection (AHR). We retrospectively studied 113 kidney transplant recipients who had negative prospective T-cell and B-cell complement-dependent cytotoxicity (CDC) crossmatches at the time of transplant. Pretransplantation sera were screened for the presence of circulating anti-HLA antibody and DSA by using highly sensitive and HLA-specific Luminex assay, and the results were correlated with AR and AHR posttransplantation. We found that approximately half of our patient population (55/113, 48.7%) had circulating anti-HLA antibody pretransplantation. Of 113 patients, 11 (9.7%) had HLA-DSA. Of 11 rejection episodes post-transplant, only two patients had pretransplantation DSA, of whom one had a severe AHR (C4d positive). One-year allograft survival was similar between the pretransplantation DSA-positive and -negative groups. Number, class, and intensity of pretransplantation DSA, as well as presensitizing events, could not predict AR. We conclude that, based on the presence of pretransplantation DSA, post-transplantation acute rejections episodes could not have been predicted. The only AHR episode occurred in a recipient with pretransplantation DSA. More work should be performed to better delineate the precise clinical significance of detecting low titers of DSA before transplantation.

Valganciclovir (VGC) is an oral prodrug of ganciclovir (GCV) recently introduced for prophylaxis and treatment of cytomegalovirus infection. Optimal concentration exposure for effective and safe VGC therapy would require either reproducible VGC absorption and GCV disposition or dosage adjustment based on therapeutic drug monitoring (TDM). We examined GCV population pharmacokinetics in solid organ transplant recipients receiving oral VGC, including the influence of clinical factors, the magnitude of variability, and its impact on efficacy and tolerability. Nonlinear mixed effect model (NONMEM) analysis was performed on plasma samples from 65 transplant recipients under VGC prophylaxis or treatment. A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by the glomerular filtration rate (GFR), patient gender, and graft type (clearance/GFR = 1.7 in kidney, 0.9 in heart, and 1.2 in lung and liver recipients) with interpatient and interoccasion variabilities of 26 and 12%, respectively. Body weight and sex influenced central volume of distribution ( V 1 = 0.34 liter/kg in males and 0.27 liter/kg in females [20% interpatient variability]). No significant drug interaction was detected. The good prophylactic efficacy and tolerability of VGC precluded the demonstration of any relationship with GCV concentrations. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of the GCV profile after treatment with oral VGC, routine TDM does not appear to be clinically indicated in solid-organ transplant recipients. However, GCV plasma measurement may still be helpful in specific clinical situations.

Cyclosporine is a substrate of cytochrome P450 (CYP) 3A and of the transporter ABCB1, for which polymorphisms have been described. In particular, CYP3A5 *3/*3 genotype results in the absence of CYP3A5 activity, whereas CYP3A7 *1/*1C genotype results in high CYP3A7 expression in adults. Log-transformed dose-adjusted cyclosporine trough concentration and daily dose per weight were compared 1, 3, 6, and 12 months after transplantation between CYP3A and ABCB1 genotypes in 73 renal (n = 64) or lung (n = 9) transplant recipients. CYP3A5 expressors (*1/*3 genotype; n = 8-10) presented significantly lower dose-adjusted cyclosporine trough concentrations (P0.05) and required significantly higher daily doses per weight (P0.01) than the nonexpressors (*3/*3 genotype; n = 55-59) 1, 3, 6, and 12 months after transplantation. In addition, 7 days after transplantation, more CYP3A5 expressors had uncorrected trough cyclosporine concentration below the target concentration of 200 ng/mL than the nonexpressors (odds ratio = 7.2; 95% confidence interval = 1.4-37.3; P = 0.009). CYP3A4 rs4646437CT influenced cyclosporine kinetics, the T carriers requiring higher cyclosporine dose. CYP3A7*1C carriers required a 1.4-fold to 1.6-fold higher cyclosporine daily dose during the first year after transplantation (P0.05). In conclusion, CYP3A4, CYP3A5, and CYP3A7 polymorphisms affect cyclosporine metabolism, and therefore, their genotyping could be useful, in association with therapeutic drug monitoring, to prospectively optimize cyclosporine prescription in transplant recipients. The administration of a CYP3A genotype-dependent cyclosporine starting dose should therefore be tested prospectively in a randomized controlled clinical trial to assess whether it leads to an improvement of the patients outcome after transplantation, with adequate immunosuppression and decreased toxicity.

Background Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials. Methods Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (≥10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN. Results No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports. Conclusions In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.

Combined liver-kidney transplantation is considered a low risk for immunologic complication. We report an unusual case of identical ABO liver-kidney recipient without preformed anti-human leukocyte antigen (HLA) antibodies, transplanted across a T- and B-cell-negative cross-match and complicated by early acute humoral and cellular rejection, first in the liver then in the kidney. While analyzing the immunologic complications in our cohort of 12 low-risk combined liver-kidney recipients, only one recipient experienced a rejection episode without detection of anti-HLA antibody over time. Although humoral or cellular rejection is rare after combined kidney-liver transplantation, our data suggest that even in low-risk recipients, the liver does not always systematically protect the kidney from acute rejection. Indeed, the detection of C4d in the liver should be carefully followed after combined liver-kidney transplantation.

The expression on lymphocytes of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene, might influence cyclosporine intracellular concentration.ABCB1 genotypes, cyclosporine intracellular and blood concentrations were determined in 64 stable renal, liver or lung transplant recipients.Cyclosporine intracellular concentration correlated moderately with blood concentration (r=0.30, P0.00005). The ABCB1 1199A carriers presented a 1.8-fold decreased cyclosporine intracellular concentration (P=0.04), whereas the 3435T carriers presented a 1.7-fold increase (P=0.02) as well as a 1.2-fold increased blood concentration (P=0.04). In contrast, ABCB1 61AG, 1236CT and 2677GT polymorphisms did not influence cyclosporine intracellular and blood concentrations.This is the first report demonstrating that ABCB1 polymorphisms influence cyclosporine intracellular concentration. Interestingly, its influence on intracellular concentration is significantly higher than on blood concentration (P0.002). This may therefore modulate cyclosporine immunosuppressive activity.

Background: Lung transplantation (LT) is a recognized treatment for end-stage pulmonary disease. Bacteria from the recipient nasopharynx seed the new lungs leading to infections and allograft damage. Understanding the characteristics and topological variations of the microbiota may be important to apprehend the pathophysiology of allograft dysfunction. Objectives: To examine the characteristics and relationship of bacterial compositions between conducting and respiratory zones of the allograft. Methods: We performed 16S rRNA gene sequencing on bronchial aspirates (BAs) and bronchoalveolar lavages (BALs) collected in pairs in 19 patients at several time-points post-LT. Results: The respiratory zone was characterized independently of the time post-LT by a higher bacterial richness than the conducting zone (p = 0.041). The phyla Firmicutes and Proteobacteria dominated both sampling zones, with an inverse correlation between these two phyla (Spearman r = -0.830). Samples of the same pair, as well as pairs from the same individual clustered together (Pseudo-F = 3.8652, p < 0.01). Microbiota of BA and BAL were more closely related in samples from the same patient than each sample type across different patients, with variation in community structure being mainly inter-individual (p < 0.01). Both number of antibiotics administered (p < 0.01) and time interval post-LT (p < 0.01) contributed to the variation in global microbiota structure. Longitudinal analysis of BA-BAL pairs of two patients showed dynamic wave like fluctuations of the microbiota. Conclusions: Our results show that post-transplant respiratory zones harbor higher bacterial richness, but overall similar bacterial profiles as compared to conductive zones. They further support an individual microbial signature following LT.

We analyzed data from all consecutive kidney transplant patients at our institution between April 2003 and October 2006. We found 15 cases of late-onset cytomegalovirus (CMV) infection, two of which developed concurrent post-transplant diabetes mellitus (PTDM). In these two cases, PTDM was transient and normal glucose tolerance was achieved after an eight-wk therapeutic course of oral valganciclovir. These findings suggest that CMV infection after organ transplantation may be associated with concurrent PTDM. The distinct causative relationship is yet to be determined.

Acute antibody-mediated rejection (acute humoral rejection; AHR) of organ allografts usually presents as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition with renal dysfunction, associated with circulating donor-specific anti-human leukocyte antigen alloantibodies, is diagnostic of AHR in kidney allografts. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), tacrolimus, mycophenolate mofetil and/or intravenous immunoglobulins, as well as rituximab or splenectomy, have been recently used to successfully treat AHR. However, the optimal protocol to treat AHR still remains to be defined. Anti-CD20+ monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as rescue therapy in some episodes of steroid- and antilymphocyte-resistant humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunological risk patients in anticipation of a previously cross-match positive (or ABO incompatible) kidney transplantation. In the near future, the possible role of new specific anti-B-cell approaches or, possibly, of new anti-T-cell activation approaches using selective agents such as belatacept should be assessed to further refine the present treatment of humoral rejection.

There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

In the general population, renal cell carcinoma (RCC) is a relatively common neoplasm; however, the papillary RCC subtype is infrequent and represents only 10 to 15% of all RCC. Angiomyolipoma is a well-known common benign tumor. The occurrence of RCC in association with angiomyolipoma is a rare event, with only approximately 50 cases reported in the nontransplantation setting. In transplant recipients, RCC can develop in native kidneys, but its occurrence "de novo" in the renal allograft is very rare with an estimated incidence of less than 0.5%. We report here the case of a 39-year-old woman who underwent cadaveric renal transplantation in 1990. No lesion was observed in the allograft during the pre- and perioperative period or on early postoperative ultrasounds. No graft rejection occurred under a standard triple immunosuppressive therapy. Thirteen years later, during a routine ultrasonography, 2 solid masses were discovered in the allograft, both of them richly vascularized. She underwent allograft nephrectomy and the histologic findings revealed that one of the tumors was a chromophilic (type 1) papillary RCC (2.5 cm in diameter) and the other, an angiomyolipoma (1.5 cm). Microsatellite analysis of the allograft, as compared with the recipient peripheral blood leukocytes, demonstrated that the 2 tumors (1 malignant and 1 benign) were of donor origin. To our knowledge, this is the first report of de novo concurrent papillary RCC and angiomyolipoma in a renal allograft.

Acute antibody-mediated rejection (acute humoral rejection [AHR]) of organ allografts presents most of the time as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition is diagnostic of AHR in kidney allografts and is associated with circulating donor-specific anti-HLA alloantibodies. Removal of alloantibodies with suppression of antibody production and rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), mycophenolate mofetil, tacrolimus, and/or intravenous immunoglobulins have been used to successfully treat AHR. The optimal protocol to treat humoral rejection remains to be defined. Anti-CD20 monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as a rescue therapy in some episodes of refractory humoral rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully "desensitize" selected high-immunologic risk patients who were in anticipation of crossmatch-positive (or ABO-incompatible) kidney transplantation. Recent data suggest that chronic kidney allograft rejection might also be monitored by complement C4d in biopsies. The efficacy and safety of immunosuppressive drugs such as tacrolimus, mycophenolate mofetil (or enteric-coated mycophenolic acid), sirolimus, or everolimus in controlling antidonor humoral responses in patients with chronic allograft dysfunction remains to be studied prospectively. The combination of tacrolimus and mycophenolate mofetil appears to effectively suppress antidonor antibody production. In the near future, the possible role of specific anti–B-cell approaches with drugs, such as rituximab, or possibly of new anti–T-cell activation approaches using selective agents such as belatacept should be assessed to refine the management of chronic allograft dysfunction.

The calcineurin inhibitors (CNIs) cyclosporine and tacrolimus have been the cornerstones of immunosuppressive strategies in clinical transplantation. Currently, regimens that are most widely used for induction and maintenance therapy include CNIs. However, many clinical trials aiming at reducing or eliminating CNIs have been performed in recent years. Here, we review and discuss current and future immunosuppressive strategies with a special emphasis on the role of CNIs, in the light of recent studies in the field of kidney transplantation. In the current era, CNIs still play an important role.

Sirolimus is a new immunosuppressive agent used to prevent rejection in renal allograft recipients in order to reduce the need of potentially nephrotoxic calcineurin inhibitors (cyclosporine, tacrolimus). The cutaneous side effects of sirolimus are not well known and they may have been underestimated. We report 2 cases of follicular acneiform eruptions induced by sirolimus in renal allograft recipients. This dermatologic complication was severe and difficult to treat, and resolved only after discontinuation of sirolimus.