New Insights on End-Stage Renal Disease and Healthy Individual Gut Bacterial Translocation: Different Carbon Composition of Lipopolysaccharides and Different Impact on Monocyte Inflammatory Response.

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.

End-Stage Renal Disease-Associated Gut Bacterial Translocation: Evolution and Impact on Chronic Inflammation and Acute Rejection After Renal Transplantation.

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.

Influence of fractalkine receptor gene polymorphisms V249I-T280M on cancer occurrence after renal transplantation.

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.

Significant increase in 1-year posttransplant renal arterial index predicts graft loss.

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.

Lymphocyte subsets in renal transplant recipients with de novo genitourinary malignancies.

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.

Metabolic syndrome and atherosclerotic events in renal transplant recipients.

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.