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Chronic kidney disease induces disruption of the intestinal epithelial barrier, leading to gut bacterial translocation. Here, we appreciated bacterial translocation by analyzing circulating lipopolysaccharides (LPS) using two methods, one measuring only active free LPS, and the other quantifying total LPS as well as LPS lipid A carbon chain length. This was done in end-stage renal disease (ESRD) patients and healthy volunteers (HV). We observed both higher LPS concentration in healthy volunteers and significant differences in composition of translocated LPS based on lipid A carbon chain length. Lower LPS activity to mass ratio and higher concentration of high-density lipoproteins were found in HV, suggesting a better plasma capacity to neutralize LPS activity. Higher serum concentrations of soluble CD14 and pro-inflammatory cytokines in ESRD patients confirmed this hypothesis. To further explore whether chronic inflammation in ESRD patients could be more related to LPS composition rather than its quantity, we tested the effect of HV and patient sera on cytokine secretion in monocyte cultures. Sera with predominance of 14-carbon chain lipid A-LPS induced higher secretion of pro-inflammatory cytokines than those with predominance of 18-carbon chain lipid A-LPS. TLR4 or LPS antagonists decreased LPS-induced cytokine production by monocytes, demonstrating an LPS-specific effect. Thereby, septic inflammation observed in ESRD patients may be not related to higher bacterial translocation, but to reduced LPS neutralization capacity and differences in translocated LPS subtypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Adda-Rezig, Carron, Pais de Barros, Choubley, Charron, Rérole, Laheurte, Louvat, Gaiffe, Simula-Faivre, Deckert, Lagrost, Saas, Ducloux and Bamoulid.)

Chronic inflammation in end-stage renal disease (ESRD) is partly attributed to gut bacterial translocation (GBT) due to loss of intestinal epithelium integrity. Increased levels of circulating lipopolysaccharide (LPS) -a surrogate marker of GBT- contribute to maintain a chronic inflammatory state. However, circulating LPS can be neutralized by lipoproteins and transported to the liver for elimination. While ESRD-associated GBT has been widely described, less is known about its changes and impact on clinical outcome after kidney transplantation (KT). One hundred and forty-six renal transplant recipients with serum samples obtained immediately before and 1 year after transplantation (1-Year post KT) were included. Intestinal epithelium integrity (iFABP), total LPS (by measuring 3-hydroxymyristate), LPS activity (biologically active LPS measured by the LAL assay), inflammatory biomarkers (sCD14 and cytokines), lipoproteins and LPS-binding proteins (LBP and phospholipid transfer protein [PLTP] activity) were simultaneously measured. At 1-Year post KT, iFABP decreased but remained higher than in normal volunteers. Total LPS concentration remained stable while LPS activity decreased. Inflammation biomarkers decreased 1-Year post KT. We concomitantly observed an increase in lipoproteins. Higher sCD14 levels before transplantation was associated with lower incidence of acute rejection. Although GBT remained stable after KT, the contemporary increase in lipoproteins could bind circulating LPS and contribute concomitantly to neutralization of LPS activity, as well as improvement in ESRD-associated chronic inflammation. Chronic exposure to LPS in ESRD could promote endotoxin tolerance and explain why patients with higher pre-transplant sCD14 are less prompt to develop acute rejection after transplantation.

Persistent ATG-induced CD4(+) T cell lymphopenia is associated with serious clinical complications. We tested the hypothesis that ATG induces accelerated immune senescence in renal transplant recipients (RTR). Immune senescence biomarkers were analyzed at transplant and one-year later in 97 incident RTR -62 patients receiving ATG and 35 receiving anti-CD25 mAb (α-CD25). This consisted in: (i) thymic output; (ii) bone marrow renewal of CD34(+) hematopoietic progenitor cells (CD34(+) HPC) and lymphoid (l-HPC) and myeloid (m-HPC) progenitor ratio; (iii) T cell phenotype; and (iv) measurement of T cell relative telomere length (RTL) and telomerase activity (RTA). Clinical correlates were analyzed with a 3 year follow-up. Thymic output significantly decreased one-year posttransplant in ATG-treated patients. ATG was associated with a significant decrease in l-HPC/m-HPC ratio. Late stage differentiated CD57(+) /CD28(-) T cells increased in ATG-treated patients. One-year posttransplant T cell RTL and RTA were consequently lower in ATG-treated patients. ATG is associated with accelerated immune senescence. Increased frequency of late differentiated CD4(+) T cell frequency at transplantation tended to be predictive of a higher risk of subsequent opportunistic infections and of acute rejection only in ATG-treated patients but this needs confirmation. Considering pretransplant immune profile may help to select those patients who may benefit from ATG to prevent severe infections and acute rejection., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Fractalkine (CX3CL1) and its receptor (CX3CR1) are involved in antitumor immunity. Two common single nucleotide polymorphisms of the CX3CR1 gene, V249I and T280M, have been associated with reduced fractalkine signaling characterized by decreased adhesive function, signaling, and chemotaxis of leukocytes. We hypothesized that a renal transplant recipient (RTR) carrying the homozygous I249M280 genotype could experience more cancer due to lower CX3CL1-dependent antitumorigenic effects., Methods: We studied the association between these polymorphisms and cancer incidence in two independent cohorts of RTR, including a total of 622 patients., Results: The median follow-up was 8.7 and 7.9 years for the first and second cohorts, respectively. Analysis of 622 patients identified 20 (3.2%) I249M280 homozygous patients, 321 (51.6%) V249T280 homozygous patients, and 281 (45.2%) heterozygous patients. I249M280 homozygotes have an independent increased risk of cancer (hazard ratio [95% confidence interval], 3.3 [1.04-10.52], P=0.043 for cohort 1 and 9.2 [1.67-50.91], P=0.011 for cohort 2) compared with other patients. Age and male gender were also risk factors for cancer occurrence., Conclusions: CX3CR1 gene polymorphism is associated with a higher rate of cancer in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management.

Background and Objectives: Conflicting data have been reported concerning the use of kidney graft arterial resistance index (RI) measured by Doppler to predict death-censored graft loss. We hypothesized that changes in RI values could carry better information than a single measure of RI., Design, Setting, Participants, & Measurements: Four hundred twenty-five renal transplant recipients were included in the study. We tested whether changes in renal arterial resistance index between 4 and 12 months after transplant (ΔRI(4→12)) were predictive of graft loss., Results: Neither 4-month nor 1-year RI predicted graft loss. The area under the receiver operating characteristics curve of ΔRI(4→12) for graft loss was 0.75. A ΔRI(4→12) ≥10% had the best sensitivity and specificity. One year after transplant, 22% of the study population had ΔRI(4→12) ≥10%. Fifty-five patients (12.9%) experienced graft loss during follow-up. The annual incidence of graft loss was higher in patients with ΔRI(4→12) ≥10% (3.5 versus 1.3%; P = 0.009). In multivariate analysis, patients with ΔRI(4→12) ≥10% had an increased risk of graft loss (hazard ratio, 6.21; 95% confidence interval, 1.99 to 22.15; P = 0.002)., Conclusions: A variation in RI ≥10% in the first year after transplant is an independent risk factor for death-censored graft loss in renal transplant recipients.

Introduction: The incidence of genitourinary tumors (GUT) in renal transplant recipients (RTR) is higher than in the general population. We previously reported that CD4 lymphocytopenia is associated with a high incidence of skin cancer in RTR. Here, we investigate whether persistent CD4 T cell lymphopenia is associated with GUT occurrence., Patients and Methods: A total of 433 patients were included in this study. All patients underwent annually systematic lymphocyte subset (CD3, CD4, CD8, CD19) determination by flow cytometry., Results and Conclusion: During the follow-up period, 13 patients developed GUT: 6 patients a prostate adenocarcinoma (incidence 0.06%/year) and 7 patients a renal cell carcinoma (incidence 0.07%/year). The patients with GUT were older than those without. Both groups did not differ in posttransplant duration, dialysis mode and duration, induction regimen, or acute rejection history. No persistent CD4 lymphopenia was observed in the patients with GUT. Although CD4 T cell lymphopenia is associated with skin cancer in long-term RTR, it did not appear to be a risk factor for GUT. This suggests that other factors encountered in the setting of kidney transplantation (e.g., immunosuppressive drugs, end-stage renal failure, etc.) favor the development of GUT in RTR., (2008 S. Karger AG, Basel)

Background: Metabolic syndrome (MS) is a known cardiovascular risk factor in the general population. We explored the influence of MS on the occurrence of atherosclerotic events (AEs) after renal transplantation., Methods: Three hundred thirty-seven renal transplant recipients were included in the study. Various parameters (e.g., anthropometric and biological) were measured 1 year after transplant., Results: One year after transplant, 32% of the study population met criteria for MS. Older age, male gender, pretransplant high body mass index, and an increase in body mass index>or=5% in the first year after transplant were predictive factors for development of MS at 1 year after transplant. Forty-two patients (12.4%) experienced AEs during the 8 years of follow-up. The cumulated incidence of AEs was greater in patients with MS compared with others without MS (25% vs. 7%; P<0.001). In multivariate analysis, patients with MS at 1 year after transplant had an increased risk of AE (hazard ratio 3.40, 95% confidence interval 1.58-7.32, P=0.002). Older age, low creatinine clearance, high C-reactive protein level, and a past history of cardiovascular disease were other independent risk factors for AE., Conclusions: Similar to the general population, MS is an independent risk factor for AE after renal transplantation. Relevant preventive measures targeting different aspects of MS would then have a potential impact on prevalence of AE in this population.

Metabolic syndrome (MS) and obesity participate in the pathogenesis of kidney disease. We explored the impact of MS and post-transplant weight gain on graft survival. Two hundred ninety-two renal transplant recipients (RTRs) were included in the study. Various parameters (e.g. anthropometric, biological) were measured at the time of transplantation as well as 1 year post-transplant. The proportion of patients with overweight or obesity significantly increased during the first year post-transplant (p = 0.04). Mean weight gain was 2.7 +/- 5.8 kg. Thirty patients (10.3%) lost their graft during follow-up. In multivariate analysis, patients with an increase in body mass index (BMI) of more than 5% at 1 year post-transplant had an increased risk of graft loss with (HR: 2.82 [95% CI: 1.11-7.44], p = 0.015) or without death censoring (HR: 2.31 [95% CI: 1.06-5.04], p = 0.035). Low creatinine clearance (HR: 4.72 [95% CI: 1.63-13.69], p = 0.004), high urinary protein excretion (HR: 3.21 [95% CI: 1.27-8.18], p = 0.014) and delayed graft function (DGF) (HR: 2.621 [95% CI: 1.07-6.39], p = 0.036) were also independent risk factors for graft loss. MS did not independently predict graft loss, partly due to significant interactions with low-grade inflammation. We conclude that post-transplant weight gain significantly reduces graft survival.