Impact of de novo donor-specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function.

BACKGROUND: This retrospective multicenter long-term cohort study investigates de novo donor-specific HLA antibodies (dnDSA) impact on allograft survival in pediatric kidney transplantation (KTx), depending on allograft function at dnDSA detection. METHODS: Seventy patients with dnDSA screening in the context of acute allograft dysfunction (AAD) (>50% serum creatinine increase) or routine follow-up were included during a 20-year period. Number of dnDSA specificities and HLA total mean fluorescence intensity (MFI-sum) were collected. RESULTS: Median follow-up time was 8.6 years. Among the 22 dnDSA+ patients, 8 patients presented AAD. Compared with dnDSA- patients, allograft survival was shorter only in dnDSA+/AAD+ patients, regardless of dnDSA detection during the 5-year post-transplant period (9 patients) or later (13 patients) (log rank p < .001 and p < .001, respectively). One dnDSA+/AAD-, 7 dnDSA+/AAD+, and 5 dnDSA- patients lost their allograft. Allograft survival was shorter in dnDSA+/AAD+ patients compared with the 16 dnDSA-/AAD+ patients (log rank p < .001) but did not differ between dnDSA+/AAD- and dnDSA-/AAD- patients (log rank p = .157). dnDSA+/AAD+ and dnDSA-/AAD+ patients presented higher risk of allograft failure compared with the other patient groups after adjustment for recipient age at KTx, donor type, and incidence of delayed graft function (HR 11.322, 95% CI 3.094-41.429, p < .001). Concurrent MFI-sum >10 000 and multiple dnDSA specificities were more significantly associated with AAD, compared with each factor separately (p < .001). CONCLUSIONS: In pediatric KTx, AAD shortens allograft survival in dnDSA+ patients, regardless of dnDSA time detection, and is commonly observed when high MFI-sum concurs with multiple dnDSA specificities. dnDSA without AAD incidence does not determinately affect allograft survival.

Histology and Immunohistochemistry of Radial Arteries Are Suggestive of an Interaction between Calcification and Early Atherosclerotic Lesions in Chronic Kidney Disease.

Background and Objectives: recent studies suggest an implication of immune mechanisms in atherosclerotic disease. In this paper, the interaction between inflammation, calcification, and atherosclerosis on the vessel walls of patients with chronic kidney disease (CKD) is described and evaluated. Materials and Methods: patients with stage V CKD, either on pre-dialysis (group A) or on hemodialysis (HD) for at least 2 years (group B), in whom a radiocephalic arteriovenous fistula (RCAVF) was created, were included in the study. The control group included healthy volunteers who received radial artery surgery after an accident. The expressions of inflammatory cells, myofibroblasts, and vascular calcification regulators on the vascular wall were estimated, and, moreover, morphometric analysis was performed. Results: the expressions of CD68(+) cells, matrix carboxyglutamic acid proteins (MGPs), the receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL), and osteoprotegerin (OPG), were significantly increased in CKD patients compared to the controls p = 0.02; p = 0.006; p = 0.01; and p = 0.006, respectively. In morphometric analysis, the I/M and L/I ratios had significant differences between CKD patients and the controls 0.3534 ± 0.20 vs. 0.1520 ± 0.865, p = 0.003, and 2.1709 ± 1.568 vs. 4.9958 ± 3.2975, p = 0.03, respectively. The independent variables correlated with the degree of vascular calcification were the intensity of CD34(+), aSMA(+) cells, and OPG, R2 = 0.76, p < 0.0001, and, with intima-media thickness (IMT), the severity of RANKL expression R2 = 0.3, p < 0.0001. Conclusion: atherosclerosis and vascular calcification in CKD seem to be strongly regulated by an immunological and inflammatory activation on the vascular wall.

Uric acid increases cellular and humoral alloimmunity in primary human peripheral blood mononuclear cells.

AIM: Hyperuricaemia is common among kidney transplant recipients and has been associated with worse graft outcome. Since episodes of acute cellular rejection and chronic humoral rejection contribute to decreased graft survival, in this study the effect of uric acid on cellular and humoral alloimmunity was evaluated. METHODS: Cellular alloimmunity was assessed by cell proliferation in two-way mixed lymphocyte reaction (MLR) with human peripheral blood mononuclear cells (PBMC). For assessing humoral alloimmunity we developed a method in which humoral alloimmunity was induced in one-way MLR. Then the de novo production of alloantibodies was measured with an antibody-mediated complement-dependent cytotoxicity assay, in which supernatants from the above MRLs were used against resting PBMC similar to the stimulator cells of the above MLRs. RESULTS: Uric acid at a concentration above its crystallization threshold increased cellular proliferation in two-way MLRs. Supernatants from one-way MLRs performed in the presence of uric acid were more cytotoxic against PBMC from individuals that had conferred the stimulator cells for the above MLRs. CONCLUSIONS: Uric acid increases both cellular and humoral alloimmunity in human PBMC. These results offer a possible pathogenetic mechanism for the observed relation between hyperuricaemia and worse kidney allograft survival.

New nucleos(t)ide analogue monoprophylaxis after cessation of hepatitis B immunoglobulin is effective against hepatitis B recurrence.

New nucleos(t)ide agents (NAs) [entecavir (ETV) and tenofovir (TDF)] have made hepatitis B immunoglobulin (HBIG)-sparing protocols an attractive approach against hepatitis B virus (HBV) recurrence after liver transplantation (LT). Twenty-eight patients transplanted for HBV cirrhosis in our centre were prospectively evaluated. After LT, each patient received HBIG (1000 IU IM/day for 7 days and then monthly for 6 months) plus ETV or TDF and then continued with ETV or TDF monoprophylaxis. All patients had undetectable HBV DNA at the time of LT, and they were followed up with laboratory tests including glomerular filtration rate (GFR) after LT. All patients (11 under ETV and 17 under TDF) remained HBsAg/HBV DNA negative during the follow-up period [median: 21 (range 9-43) months]. GFR was not different between TDF and ETV groups of patients at 6 and 12 months and last follow-up (P value >0.05 for all comparisons). The two groups of patients were similar regarding their ratio of maximum rate of tubular phosphate reabsorption to the GFR (TmP/GFR). In conclusion, in this prospective study, we showed for the first time that maintenance therapy with ETV or TDF monoprophylaxis after 6 months of low-dose HBIG plus ETV or TDF after LT is highly effective and safe.

Artificial kidney: Challenges and opportunities.

This review aims to present the developments occurring in the field of artificial organs and particularly focuses on the presentation of developments in artificial kidneys. The challenges for biomedical engineering involved in overcoming the potential difficulties are showcased, as well as the importance of interdisciplinary collaboration in this marriage of medicine and technology. In this review, modern artificial kidneys and the research efforts trying to provide and promise artificial kidneys are presented. But what are the problems faced by each technology and to what extent is the effort enough to date?

Evaluation of Regulatory B Cell Subpopulations CD24++CD38++, CD24++CD27+, Plasmablasts and Their Correlation with T Regs CD3+CD4+CD25+FOXP3+ in Dialysis Patients and Early Post-Transplant Rejection-Free Kidney Recipients.

Background: B and T regulatory cells, also known as Bregs and Tregs, are involved in kidney transplantation. The purpose of this study is to monitor changes in the frequency and absolute numbers of Tregs (CD3+CD4+CD25+FoxP3+), transitional Bregs (tBregs) (CD24++CD38++), memory Bregs (mBregs) (CD24++CD27+), and plasmablasts before (T0) and six months (T6) after transplantation. Additionally, we aim to investigate any correlation between Tregs and tBregs, mBregs, or plasmablasts and their relationship with graft function. Methods: Flow cytometry was used to immunophenotype cells from 50 kidney recipients who did not experience rejection. Renal function was assessed using the estimated glomerular filtration rate (eGFR). Results: At T6, there was a significant decrease in the frequency of Tregs, plasmablasts, and tBregs, as well as in the absolute number of tBregs. The frequency of mBregs, however, remained unchanged. Graft function was found to have a positive correlation with the frequency of tBregs and plasmablasts. A significant correlation was observed between the frequency and absolute number of tBregs only when the eGFR was greater than 60 but not at lower values. At an eGFR greater than 60, there was a positive correlation between the absolute numbers of Tregs and mBregs but not between Tregs and tBregs. No correlation was observed for any cell population in dialysis patients. Conclusions: The data show a correlation between the frequency and absolute number of tBregs and the absolute number of Tregs and mBregs with good renal function in the early post-transplant period.

Impact and management of COVID-19 in liver transplant candidates and recipients.

The COVID-19 outbreak has had severe consequences for global public health, medical communities, and the socioeconomic status of a considerable number of countries. The emergence of COVID-19 has also significantly impacted the world of liver transplantation (LT). Studies from transplantation centers around the world have shown that LTs during the COVID-19 pandemic have been restricted because of the high risk of serious COVID-19 infection in this population. According to the Centers for Disease Control and Prevention, patients with liver disease are considered at higher risk for severe COVID-19 infection. In March 2020, the American Association for the Study of Liver Diseases recommended that LT should be limited to emergency cases. The COVID-19 treatment guidelines published by the National Institutes of Health are being constantly updated according to new epidemiology trends and treatment regimens. Immunocompromised patients have a higher risk of developing severe disease or death from COVID-19 compared with the general population. In this review, we summarize the available evidence regarding treatment guidelines and considerations for the evaluation and management of LT candidates and recipients in the era of COVID-19. In addition, we present data regarding COVID-19 among LT patients in our local transplantation center.

Exploring Perturbations in Peripheral B Cell Memory Subpopulations Early after Kidney Transplantation Using Unsupervised Machine Learning.

BACKGROUND: B cells have a significant role in transplantation. We examined the distribution of memory subpopulations (MBCs) and naïve B cell (NBCs) phenotypes in patients soon after kidney transplantation. Unsupervised machine learning cluster analysis is used to determine the association between the cellular phenotypes and renal function. METHODS: MBC subpopulations and NBCs from 47 stable renal transplant recipients were characterized by flow cytometry just before (T0) and 6 months after (T6) transplantation. T0 and T6 measurements were compared, and clusters of patients with similar cellular phenotypic profiles at T6 were identified. Two clusters, clusters 1 and 2, were formed, and the glomerular filtration rate was estimated (eGFR) for these clusters. RESULTS: A significant increase in NBC frequency was observed between T0 and T6, with no statistically significant differences in the MBC subpopulations. Cluster 1 was characterized by a predominance of the NBC phenotype with a lower frequency of MBCs, whereas cluster 2 was characterized by a high frequency of MBCs and a lower frequency of NBCs. With regard to eGFR, cluster 1 showed a higher value compared to cluster 2. CONCLUSIONS: Transplanted kidney patients can be stratified into clusters based on the combination of heterogeneity of MBC phenotype, NBCs and eGFR using unsupervised machine learning.

Inhibition of γδ-TcR or IL17a Reduces T-Cell and Neutrophil Infiltration after Ischemia/Reperfusion Injury in Mouse Liver.

Neutrophil and T-cell recruitment contribute to hepatic ischemia/reperfusion injury. The initial inflammatory response is orchestrated by Kupffer cells and liver sinusoid endothelial cells. However, other cell types, including γδ-Τ cells, seem to be key mediators in further inflammatory cell recruitment and proinflammatory cytokine release, including IL17a. In this study, we used an in vivo model of partial hepatic ischemia/reperfusion injury (IRI) to investigate the role of the γδ-Τ-cell receptor (γδTcR) and the role of IL17a in the pathogenesis of liver injury. Forty C57BL6 mice were subjected to 60 min of ischemia followed by 6 h of reperfusion (RN 6339/2/2016). Pretreatment with either anti-γδΤcR antibodies or anti-IL17a antibodies resulted in a reduction in histological and biochemical markers of liver injury as well as neutrophil and T-cell infiltration, inflammatory cytokine production and the downregulation of c-Jun and NF-κΒ. Overall, neutralizing either γδTcR or IL17a seems to have a protective role in liver IRI.

Volumetric assessment of hepatic grafts using a light detection and ranging system for 3D scanning: Preliminary data.

BACKGROUND: Liver transplantation has evolved into a safe life-saving operation and remains the golden standard in the treatment of end stage liver disease. The main limiting factor in the application of liver transplantation is graft shortage. Many strategies have been developed in order to alleviate graft shortage, such as living donor partial liver transplantation and split liver transplantation for adult and pediatric patients. In these strategies, liver volume assessment is of paramount importance, as size mismatch can have severe consequences in the success of liver transplantation. AIM: To evaluate the safety, feasibility, and accuracy of light detection and ranging (LIDAR) 3D photography in the prediction of whole liver graft volume and mass. METHODS: Seven liver grafts procured for orthotopic liver transplantation from brain deceased donors were prospectively measured with an LIDAR handheld camera and their mass was calculated and compared to their actual weight. RESULTS: The mean error of all measurements was 17.03 g (range 3.56-59.33 g). Statistical analysis of the data yielded a Pearson correlation coefficient index of 0.9968, indicating a strong correlation between the values and a Student's t-test P value of 0.26. Mean accuracy of the measurements was calculated at 97.88%. CONCLUSION: Our preliminary data indicate that LIDAR scanning of liver grafts is a safe, cost-effective, and feasible method of ex vivo determination of whole liver volume and mass. More data are needed to determine the precision and accuracy of this method.

Effects of an active lifestyle on the physical frailty of liver transplant candidates.

BACKGROUND: Liver transplantation is the most important therapeutic intervention for end-stage liver disease (ELD). The prioritization of these patients is based on the model for end-stage liver disease (MELD), which can successfully predict short-term mortality. However, despite its great validity and value, it cannot fully incor porate several comorbidities of liver disease, such as sarcopenia and physical frailty, variables that can sufficiently influence the survival of such patients. Subsequently, there is growing interest in the importance of physical frailty in regard to mortality in liver transplant candidates and recipients, as well as its role in improving their survival rates. AIM: To evaluate the effects of an active lifestyle on physical frailty on liver transplant candidates. METHODS: An observational study was performed within the facilities of the Department of Transplant Surgery of Aristotle University of Thessaloniki. Twenty liver tran splant candidate patients from the waiting list of the department were included in the study. Patients that were bedridden, had recent cardiovascular incidents, or had required inpatient treatment for more than 5 d in the last 6 mo were excluded from the study. The following variables were evaluated: Activity level via the International Physical Activity Questionnaire (IPAQ); functional capacity via the 6-min walking test (6MWT) and cardiopulmonary exercise testing; and physical frailty via the Liver Frailty Index (LFI). RESULTS: According to their responses in the IPAQ, patients were divided into the following two groups based on their activity level: Active group (A, 10 patients); and sedentary group (S, 10 patients). Comparing mean values of the recorded variables showed the following results: MELD (A: 12.05 ± 5.63 vs S: 13.99 ± 3.60; P > 0.05); peak oxygen uptake (A: 29.78 ± 6.07 mL/kg/min vs S: 18.11 ± 3.39 mL/kg/min; P < 0.001); anaerobic threshold (A: 16.71 ± 2.17 mL/kg/min vs S: 13.96 ± 1.45 mL/kg/min; P < 0.01); 6MWT (A: 458.2 ± 57.5 m vs S: 324.7 ± 55.8 m; P < 0.001); and LFI (A: 3.75 ± 0.31 vs S: 4.42 ± 0.32; P < 0.001). CONCLUSION: An active lifestyle can be associated with better musculoskeletal and functional capacity, while simultaneously preventing the evolution of physical frailty in liver transplant candidates. This effect appears to be independent of the liver disease severity.

Enhanced recovery after surgery in liver transplantation: Challenges and feasibility.

BACKGROUND: Enhanced recovery after surgery (ERAS) started a revolution that changed age-old surgical stereotypical practices regarding the overall management of the surgical patient. In the last decade, ERAS has gained significant acceptance in the community of general surgery, in addition to several other surgical specialties, as the evidence of its advantages continues to grow. One of the last remaining fields, given its significant complexity and intricate nature, is liver transplantation (LT). AIM: To investigate the existing efforts at implementing ERAS in LT. METHODS: We conducted a systematic review of the existing studies that evaluate ERAS in orthotopic LT, with a multimodal approach and focusing on measurable clinical primary endpoints, namely length of hospital stay. RESULTS: All studies demonstrated a considerable decrease in length of hospital stay, with no readmission or negative impact of the ERAS protocol applied to the postoperative course. CONCLUSIONS: ERAS is a well-validated multimodal approach for almost all types of surgical procedures, and its future in selected LT patients seems promising, as the preliminary results advocate for the safety and efficacy of ERAS in the field of LT.

Effect of panel reactive antibodies on T cell immunity reinstatement following renal transplantation.

BACKGROUND: Chronic kidney disease is associated with immunological disorders, presented as phenotypic alterations of T lymphocytes. These changes are expected to be restored after a successful renal transplantation; however, additional parameters may contribute to this process. AIM: To evaluate the impact of positive panel reactive antibodies (PRAs) on the restoration of T cell phenotype, after renal transplantation. METHODS: CD4CD28null, CD8CD28null, natural killer cells (NKs), and regulatory T cells (Tregs) were estimated by flow cytometry at T0, T3, and T6 which were the time of transplantation, and 3- and 6-mo follow-up, respectively. Changes were esti mated regarding the presence or absence of PRAs. RESULTS: Patients were classified in two groups: PRA(-) (n = 43) and PRA(+) (n = 28) groups. Lymphocyte and their subtypes were similar between the two groups at T0, whereas their percentage was increased at T3 in PRA(-) compared to PRA(+) [23 (10.9-47.9) vs 16.4 (7.5-36.8 µ/L, respectively; P = 0.03]. Lymphocyte changes in PRA(-) patients included a significant increase in CD4 cells (P < 0.0001), CD8 cells (P < 0.0001), and Tregs (P < 0.0001), and a reduction of NKs (P < 0.0001). PRA(+) patients showed an increase in CD4 (P = 0.008) and CD8 (P = 0.0001), and a reduction in NKs (P = 0.07). CD4CD28null and CD8CD28null cells, although initially reduced in both groups, were stabilized thereafter. CONCLUSION: Our study described important differences in the immune response between PRA(+) and PRA(-) patients with changes in lymphocytes and lymphocyte subpopulations. PRA(+) patients seemed to have a worse immune profile after 6 mo follow-up, regardless of renal function.

HCC influence on patient survival after liver transplantation for HDV cirrhosis.

BACKGROUND/AIMS: The effect of hepatocellular cancer (HCC) in patients transplanted for hepatitis B and D virus (HB/DV) cirrhosis is not well studied. Our aim was to study the long-term survival outcomes of patients who underwent liver transplantation for HB/DV cirrhosis with and without HCC. METHODOLOGY: A total of 231 primary, adult, single- organ liver transplants were performed from 1990 to 2007. HB/DV was the cause of cirrhosis in 36 patients. Nine patients died during the first 3 postoperative months from surgical complications. The study group comprised the remaining 27 patients. The median follow-up was 1515 days. RESULTS: The mean patient survival was 3760 days (95% CI: 3013-4507). Six patients were diagnosed with HCC. The mean patient survival was 3011 days (95% CI: 2344-3679) and 4036 days (95% CI: 3002-5070) for recipients without and with HCC, respectively. For the same groups, the incidence of microbial infections was 61.9% and 33.3%, respectively (p=0.219). HCC has not recurred in any of the six patients. CONCLUSIONS: The mean long-term survival after liver transplantation for HB/DV and HCC surpassed 11 years. The superior survival of HCC patients is difficult to explain. The increased number (almost double) of microbial infections in the non- HCC population might be held accountable.

The effect of anti­HLA class I antibodies on the immunological properties of human glomerular endothelial cells and their modification by mTOR inhibition or GCN2 kinase activation.

In antibody­mediated rejection (ABMR), the graft endothelium is at the forefront of the kidney transplant against the assault from the recipient's humoral immune system, and is a target of the latter. The present study investigated the effect of antibodies against human leukocyte antigen (HLA) class I (anti­HLAI) on the immunological properties of human glomerular endothelial cells. Additionally, the effect of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) inhibitor (everolimus), or the general control nonderepressible 2 kinase (GCN2K) activator (halofuginone) on anti­HLAI antibody­mediated alterations was assessed. Cell integrity was examined, an lactate dehydrogenase (LDH) release assay was performed and cleaved caspase­3 levels were determined. Furthermore, cell proliferation was analyzed by performing a bromodeoxyuridine assay and the cellular proteins involved in signal transduction or immune effector mechanisms were assessed via western blotting. IL­8, monocyte chemoattractive protein­1 (MCP­1), von Willebrand factor (vWF) and transforming growth factor­beta 1 (TGF­ß1) were assayed via ELISA. The results revealed that anti­HLAI triggered integrin signaling, activated mTOR and GCN2K, preserved cell integrity and promoted cell proliferation. Additionally, by increasing intercellular adhesion molecule 1 (ICAM­1), HLA­DR, IL­8 and MCP­1 levels, anti­HLAI enhanced the ability of immune cells to interact with endothelial cells thus facilitating graft rejection. Contrarily, by upregulating CD46 and CD59, anti­HLAI rendered the endothelium less vulnerable to complement­mediated injury. Finally, by enhancing vWF and TGF­ß1, anti­HLAI may render the endothelium prothrombotic and facilitate fibrosis and graft failure, respectively. According to our results, mTORC1 inhibition and GCN2K activation may prove useful pharmaceutical targets, as they prevent cell proliferation and downregulate ICAM­1, IL­8, MCP­1 and TGF­ß1. mTORC1 inhibition also decreases vWF.

Attenuation of liver ischemia/reperfusion induced apoptosis by epigallocatechin-3-gallate via down-regulation of NF-kappaB and c-Jun expression.

INTRODUCTION: Hepatic ischemia/reperfusion (I/R) activates Kupffer cells and initiates severe oxidative stress with enhanced production of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha). ROS and TNF-alpha mediate the expression of nuclear factors and kinases, activating the signal transduction pathway, and triggering apoptosis. The aim of our study was to evaluate the potential protective effect of (-)-epigallocatechin-3-gallate (EGCG) administration in inhibition of apoptosis by attenuating the expression of NF-kappaB, c-Jun, and caspase-3 in a model of severe hepatic I/R. MATERIALS AND METHODS: Thirty Wistar rats were allocated into three groups. Sham operation, I/R, and I/R-EGCG 50mg/kg. Hepatic ischemia was induced for 60min by Pringle's maneuver. Malondialdehyde (MDA), myeloperoxidase (MPO), light histology, scanning electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunocytochemistry for NF-kappaB, c-Jun, caspase-3, analysis on liver specimens and aspartate (AST), and alanine (ALT) transferases analysis in serum, were performed 120min after reperfusion. RESULTS: Apoptosis as indicated by TUNEL and caspase-3 was widely expressed in the I/R group but very limited in the EGCG treated group. Liver was stained positive for NF-kappaB and c-Jun in the I/R group but failed to be stained positive in the EGCG treated group. MDA, MPO, AST, and ALT showed marked increase in the I/R group and significant decrease in EGCG treated group. Significant alterations of liver specimens were observed by light histology and transmission electron microscopy whilst pretreatment with EGCG resulted in parenchymal preservation. CONCLUSIONS: Administration of EGCG is likely to inhibit I/R-induced apoptosis and protect liver by down-regulating NF-kappaB and c-Jun signal transduction pathways.

Vitamin D receptor activators and response to injury in kidney diseases.

Clinical studies have confirmed that administration of vitamin D receptor (VDR) activators offers a survival benefit in hemodialysis patients and may help in preservation of renal function in predialysis patients. Accumulated clinical and mainly experimental data support that in the context of kidney disease, VDR activators exert their beneficial effect not only due to their action on calcium and phosphorus homeostasis, but also through modulation of the response to injury. They attenuate systemic and renal inflammation, and they affect the tissue repair process, reducing renal fibrosis. This aspect of the functions of VDR activators in kidney disease is reviewed in the present manuscript.

Is everolimus linked to metabolic syndrome in liver transplant recipients?

BACKGROUND: As the mortality rates after liver transplantation (LT) have been reduced, the attention has shifted to additional conditions which still compromise the quality of life and the survival of these patients, such as the post-LT metabolic syndrome (MS). In order to determine the prevalence and the factors associated with the post-LT MS, we carried out the present study. METHODS: One hundred and six LT recipients, after completing at least 1 year follow up after LT, were included in the study. Data on clinical, laboratory parameters and immunosuppressive therapy before and after LT were recorded. MS was defined as per current diagnostic criteria. RESULTS: MS was prevalent in 47.2% (50 of 106 patients) and was not associated with the LT indications and the time period after LT. Univariate analysis showed that history of diabetes mellitus before (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.046-9.918, p = 0.042) and after LT (OR 6.03, 95% CI 2.18-16.67, p = 0.001), the age at the time of baseline visit (OR 1.077, 95% CI 1.033-1.124, p = 0.001) and the everolimus-based immunosuppression (OR 1.23, 95% CI 1.003-1.33, p = 0.019) were significantly associated with MS. Notably, everolimus administration was the only factor independently associated with the presence of post-LT MS (OR 1.026, 95% CI 1.004-1.047, p = 0.019). More specifically, everolimus was linked to the presence of arterial hypertension (OR 1.02, 95% CI 1.0-1.03, p = 0.05) and hyperlipidemia (OR 2.87, 95% CI 1.28-6.56, p = 0.011). CONCLUSIONS: Our study demonstrated for the first time that everolimus was independently associated with post-LT MS. Nevertheless, more robust studies are required to confirm these findings.

Everolimus with or without mycophenolate mofetil in a liver transplantation setting: a single-center experience.

BACKGROUND: This study evaluated the efficacy, safety, and impact on renal function of everolimus in patients after liver transplantation (LT) with or without mycophenolate mofetil (MMF). METHODS: We evaluated LT recipients with calcineurin inhibitor (CNI)-related renal dysfunction after everolimus initiation. Laboratory data, including evaluation of renal function based on glomerular filtration rate (GFR) at baseline (i.e., everolimus initiation) and at the end of follow up, were analyzed. RESULTS: Fifty consecutive patients started taking everolimus at 30 months post-LT (range: 1-240), 6 as monotherapy and 44 in combination with MMF. After 30.5 months (range: 6-112), all patients were alive, without any biochemical evidence of a rejection episode or recurrence of hepatocellular carcinoma. The mean GFR, based on the Modification of Diet in Renal Disease equation, was 53±13 mL/min at baseline and 59±12 mL/min at the end of follow up (P=0.031). Eleven (22%) of the patients had GFR <60 mL/min at baseline but returned to GFR >60 mL/min by the end of follow up. In multivariate analysis, the time between the development of renal dysfunction and everolimus initiation was the only factor independently associated with GFR improvement (odds ratio [OR] 0.85, 95% confidence interval [95%CI] 0.76-0.96; P=0.007). Everolimus was stopped in 11 patients (22%) at the end of follow up because of adverse events. CONCLUSION: A CNI-free everolimus-based regimen was effective in LT recipients with renal dysfunction and was associated with an improvement in GFR.