Fractional excretion of tumor necrosis factor receptor 1 and 2 in patients with type 2 diabetes and normal renal function.

AIMS/INTRODUCTION: Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin-to-creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. MATERIALS AND METHODS: This was a cross-sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2 . The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. RESULTS: Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60-89 mL/min/1.73 m2 , and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60-89 mL/min/1.73 m2 ) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. CONCLUSIONS: The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

Differential regulation of TNF receptors in maternal leukocytes is associated with severe preterm preeclampsia.

We tested the hypothesis that maternal peripheral blood leukocytes contribute to elevated levels of soluble TNF receptors (sTNFR) in preeclampsia (PE) with concomitant intrauterine growth restriction (IUGR). TNFR1 and TNFR2 were evaluated in a cross-sectional study comparing preeclamptic (n = 15) with or without IUGR versus normotensive pregnant women (PREG, n = 30), and non-pregnant controls (Con; n = 20). Plasma levels of sTNFR1 were higher in PE (1675.0 ± 227.1 pg/mL) compared with PREG (1035.0 ± 101.1 pg/mL) and Con (589.3 ± 82.67 pg/mL), with the highest values observed in PE with IUGR (2624.0 ± 421.4 pg/mL; n = 6). Plasma sTNFR2 was higher during pregnancy (PE: 1836.0 ± 198.7 pg/mL; PREG: 1697.0 ± 95.0 pg/mL) compared with Con (598.3 ± 82.7 pg/mL). Urinary levels of sTNFR1 and sTNFR2 were higher in PE and PREG compared with the Con group. Abundance of TNFR1 mRNA in peripheral blood leukocytes was strongly correlated with plasma levels of sTNFR1 in PE. However, TNFR2 mRNA accumulation in leukocytes did not correlate with sTNFR2 plasma levels. The level of sTNFR1 in plasma was correlated with body weight of the newborn (r = -0.56). The data suggest that maternal leukocytes contribute to sTNFR1 levels in plasma in association with decreasing newborn weight and PE with concomitant IUGR.

Predictive value of conjointly examined IL-1ra, TNF-R I, TNF-R II, and RANTES in patients with primary glomerulonephritis.

Interleukin-1 receptor antagonist (IL-1ra), tumor necrosis factor soluble receptors (sTNF-R) type I and II, and regulated upon activation, normal T-cell expressed and secreted (RANTES) play an important role in the modulation of primary glomerulonephritis (GN) course. The aim of the study was to assess whether pre-treatment measurements of IL-1ra, sTNF-R, and RANTES assessed conjointly may be useful as predicting factors in patients with GN. In 84 patients (45 males and 39 female) serum concentration (pg/mL) and urinary excretion (pg/mgCr) of cytokines were measured. After 12 months of therapy with steroids and cyclophosphamide the patients were divided into two subgroups: Responders (R) and Non-Responders (NR) according to the treatment results. The urinary IL-1ra, TNF-RI and RII were significantly higher in R than NR (1,732 vs 646 with P < 0.001, 13.1 vs 6.3 with P = 0.005, and 33.6 vs 14.4 with P = 0.012). The urinary RANTES excretion was increased in NR (79.6 vs 28.5; P < 0.001). The multivariable analysis showed that if conjointly assessed, only urinary IL-1ra, TNF-R I and R II, RANTES with 85% probability pointed the feature remission (R). In conclusion, the urinary excretion of IL-1ra, TNF-R I and R II, and RANTES examined conjointly are effective in predicting favorable response to immunosuppressive treatment in patients with GN.

Urinary chemokines and anti-inflammatory molecules in renal transplanted patients as potential biomarkers of graft function: a prospective study.

PURPOSE: Clinical- and histopathology-based scores are the limited predictors of allograft outcome. Thus, predictors of allograft survival still remain a challenge. This study aimed to evaluate the urinary levels of chemokines and anti-inflammatory molecules at 30, 90, and 300 days after renal transplantation and to further correlate these measurements to graft function. METHODS: Glomerular filtration rate (GFR) and urinary levels of MCP-1/CCL2, MIP-1α/CCL3, RANTES/CCL5, IL-8/CXCL8, IP-10/CXCL10, interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor-1, and receptor-2 were determined at 30, 90, and 300 days after renal transplantation in 22 patients. Transplanted patients were also divided according to the type of donor (living donor, LD, n = 13 or deceased donor, DD, n = 9). RESULTS: Urinary levels of all molecules, except MIP-1α/CCL3, remained unchanged at 30, 90, and 300 days after transplantation in our 22 patients. MIP-1α/CCL3 levels significantly reduced from 30 to 300 days and showed a negative correlation with GFR at 30 days. The comparison between LD and DD groups showed similar levels of all markers, except for MCP-1/CCL2, which presented higher values in LD than in DD at 30 days. sTNFR1 and MCP-1/CCL2 significantly reduced from 30 to 300 days in LD group, but only sTNFR2 concentrations at 30 days were negatively correlated with GFR at 300 days. On the other hand, in DD group, IL-1Ra concentrations at 30 and at 90 days were positively correlated with GFR at 300 days. CONCLUSION: Urinary chemokine and anti-inflammatory molecules measurements may be a promising tool in the follow-up of renal transplanted patients.

Mechanisms of immune complex-mediated experimental glomerulonephritis: possible role of the balance between endogenous TNF and soluble TNF receptor type 2.

In an experimental model of immune-complex-mediated glomerulonephritis, mice excreted increased levels of urinary protein starting three days after the induction. Mice lacking the TNF receptor type 2 (TNFR2) were protected from early proteinuria and enhanced mortality. Analysis of the molecular basis of the mechanisms of glomerulonephritis revealed that naïve mice continuously excrete soluble TNF-neutralizing TNFR2 in urine. Mice kept in a specific pathogen-free environment did not go on to develop early proteinuria or enhanced mortality, following induction of glomerulonephritis. TNFR2-deficient mice were protected from early proteinuria and enhanced mortality only when housed conventionally. Mice producing human TNFR2 that can be activated by mouse TNF, in addition to mouse TNFR2, did not demonstrate enhanced susceptibility to the lethal effects of glomerulonephritis, indicating that pro-inflammatory signalling via TNFR2 does not account for a sensitizing effect. Finally, we suggest that the protective effect seen in mice lacking TNFR2 results rather from environment-induced attenuation by low dose bacterial endotoxins than from missing pro-inflammatory signalling via the TNFR2.

Elevated urinary sVCAM-1, IL6, sIL6R and TNFR1 concentrations indicate acute kidney transplant rejection in the first 2 weeks after transplantation.

We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p<0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p<0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes.

Determination of soluble tumor necrosis factor-α receptor type I (TNFRI) and II (TNFRII) in the urine of healthy Japanese subjects.

We determined the urinary soluble tumor necrosis factor-α receptor type I (sTNFRI) and type II (sTNFRII) levels in healthy Japanese individuals to establish a reference value by means of specific ELISA. It was found that there were no significant differences between the urine sTNFRI and sTNFRII levels of children and adults. To demonstrate the usefulness of the reference value for children, we measured the urine sTNFRI and sTNFRII levels of children with diarrhea positive (D+) hemolytic uremic syndrome (HUS) as a preliminary study. The urine sTNFRI and sTNFRII levels of the patients with HUS were markedly higher than those of healthy children from the onset of D + HUS. Our reliable reference value for healthy children will allow us to discriminate between normal and pathological conditions in future studies.

Cell salvage alters the systemic inflammatory response after off-pump coronary artery bypass grafting surgery.

BACKGROUND: Retransfused cardiotomy suction blood contains elevated inflammatory markers and is a bypass independent source of inflammatory mediators. We hypothesized that, during off-pump coronary artery bypass (OPCAB) grafting surgery, avoiding retransfusion of unwashed cardiotomy suction blood would beneficially alter both urinary and plasma cytokine concentrations and be renoprotective. METHODS: Thirty-seven OPCAB surgery patients were randomly allocated to control (retransfusion of unwashed shed blood) and treatment (retransfusion of washed shed blood or discarding of unwashed blood) groups. Over 72 hours we measured plasma (tumor necrosis factor-alpha [TNF-alpha], interleukin-8, interleukin-6, interleukin-10, TNF soluble receptor-2, and interleukin-1 receptor antagonist) and urinary TNF soluble receptor-2 and interleukin-1 receptor antagonist and markers of renal injury and dysfunction (N-acetyl beta D glucosaminidase and alpha1-microglobulin). RESULTS: We demonstrated elevated proinflammatory cytokines in cardiotomy suction blood, which were effectively eliminated by cell salvage. After retransfusion, in comparison with controls, the treatment group had reduced plasma TNF soluble receptor-2. As compared with controls, treatment group patients also demonstrated significantly reduced levels of the urinary anti-inflammatory cytokine TNF soluble receptor-2. There were no between group differences in markers of renal injury or dysfunction. CONCLUSIONS: We have demonstrated that the management of shed mediastinal blood alters perioperative, systemic, plasma and urinary cytokine homeostasis at OPCAB surgery but does not impact on subclinical renal injury or dysfunction in this low risk group of patients.