Elevated vascular endothelial growth factor levels in the urine of patients with minimal-change nephrotic syndrome

BACKGROUND: Vascular endothelial growth factor (VEGF) is a selective endothelial mitogen and vascular permeability factor (VPF), that is mainly produced by activated monocytes/macrophages and T cells. To our knowledge, very little is known about the involvement of VEGF in minimal-change nephrotic syndrome (MCNS). The aim here was to define further the involvement of VEGF in MCNS. PATIENTS AND METHODS: Urine samples were obtained from 20 MCNS patients. The disease controls included 20 patients with IgA nephropathy (IgAN). The samples were assayed for VEGF protein by a sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with normal controls, markedly increased urinary levels of VEGF were detected in both MCNS and IgAN patients with the nephrotic syndrome (NS). The urinary VEGF (uVEGF) levels correlated with the degree ofproteinuria in MCNS and IgAN patients. Moreover, when individual MCNS patients were followed through their clinical illness, uVEGF levels were increased during the active phase and decreased as the patients went into remission. Our main concern is to distinguish between two possibilities: Increases in uVEGF excretion might indeed relate to specific glomerular pathology and thus have a pathophysiological role. Alternatively, uVEGF may be derived from the circulation and as such may be nothing more than an assay for proteinuria. In fact, given the strict correlation between uVEGF excretion and the amount of proteinuria, the second possibility appears quite conceivable. CONCLUSION: Therefore, this may be a coincidental finding which has no bearing on the pathophysiology of MCNS.     

Elevated serum interleukin-18 levels might reflect the high risk of hospitalization in patients on peritoneal dialysis

BACKGROUND: Interleukin (IL)-18 is a potent pro-inflammatory cytokine and plays a central role in atherosclerotic plaque rupture and accelerates atherosclerosis. AIM: The aim of this study was to determine serum IL-18 levels in patients on peritoneal dialysis (PD) and to assess their relationship with hospitalization. METHODS: Forty-three PD patients and 20 healthy individuals were enrolled in this study. We investigated the relationship of the serum concentrations of IL-18 and other well-established atherosclerotic markers, such as asymmetric dimethylarginine (ADMA). Hospitalization data from over a 18-month period were prospectively obtained on all 43 PD patients. Classic factors were entered into a Cox regression model to predict first hospitalization. RESULTS: The serum levels of IL-18 in patients on PD were significantly higher than those of healthy individuals (228.5 +/- 140.3 pg/mL vs 154.8 +/- 44.7 pg/mL, P < 0.05, respectively). Furthermore, serum IL-18 levels showed a positive correlation with duration of PD, serum beta2 microglobulin and serum ADMA levels. Mean serum levels of IL-18 were significantly higher among patients who had experienced at least one hospitalization than those who had not (279.9 +/- 164.3 vs 158.5 +/- 43.9 pg/mL, P = 0.0426). Furthermore, the relative risk for first hospitalization for each increase in IL-18 (pg/mL) levels was associated with a 1.182 (95% confidence interval, 1.012-1.364; P = 0.0071) increase in the risk for future hospitalization events. CONCLUSION: The present study suggests the elevated serum IL-18 levels might increase the risk for future hospitalization in patients on PD.     

Augmented interleukin-18 production by peripheral blood monocytes in patients with minimal-change nephrotic syndrome

BACKGROUND/AIM: The etiology of minimal-change nephrotic syndrome (MCNS) is poorly understood. It has been proposed that cell-mediated immunity and T-cell activation are key features of this glomerular disease. Interleukin (IL)-18, a novel interferon-gamma-stimulating factor, may act as an important effector molecule involved in various immune responses. To our knowledge, very little is known about the involvement of IL-18 in NCNS. The aim here was to define further the involvement of IL-18 in MCNS. METHODS: To understand the role of this cytokine, in vitro IL-18 levels were analyzed by a sensitive enzyme-linked immunosorbent assay (ELISA) method in 16 patients with MCNS who were either in a stable or active condition. The disease controls included 16 patients with IgA nephropathy (IgAN). The IL-18 levels were compared with values in healthy controls. RESULTS: Significantly increased spontaneous and lipopolysaccharide (LPS)-stimulated production of IL-18 was detected in peripheral blood monocyte (PBM) cultures of MCNS patients with the nephrotic syndrome (NS) as compared with those of normal controls. Moreover, when individual MCNS patients were followed through their clinical illness, IL-18 levels were increased during the active phase and normalized as the patients went into remission. The amounts of IL-18 are significantly correlated with the levels of vascular permeability factor (VPF) in MCNS patients. CONCLUSIONS: Thus, in MCNS patients, the level of IL-18 was increased and this increase was related to the activity of this disease. The data provide circumstantial evidence for a role of IL-18 in MCNS.     

Serum and urine soluble interleukin-2 receptor in idiopathic nephrotic syndrome

Although a cellular immune pathogenesis is suspected in idiopathic nephrotic syndrome of childhood (INS), there is scant direct evidence of in vivo immune activation. In order to investigate cytokine cascade activation in INS, soluble interleukin-2 receptor (sIL-2R) in plasma and urine was characterized and its levels measured in INS patients during relapse. Immunochemically detectable sIL-2R had a molecular mass of 35–46 kDa in both serum and urine and the molecule appears to be excreted intact; the pI was 5.05. INS patients had elevated serum sIL-2R levels compared with adult normal controls (845±97 vs. 373±47 U/ml,P=0.001) and were significantly higher than previously published age-matched controls. Urinary excretion of sIL-2R was 47.2±13 U/mg creatinine in patients. Both the sIL-2R excretion rate and the fractional excretion of sIL-2R were positively correlated with the excretion of albumin (P=0.02 and 0.002, respectively). These increased serum and urine levels occurred whether relapse was or was not associated with an intercurrent illness. We conclude that: (1) despite increased sIL-2R excretion during INS relapse, serum levels are significantly elevated; (2) while the elevated urinary levels could result from enhanced intrarenal production, they more likely reflect the increased serum levels; (3) the elevated sIL-2R levels support an immune pathogenesis in INS.     

Elevated serum levels of soluble interleukin-4 receptor in osteoarthritis

OBJECTIVE: To test the importance of the interleukin-4 (IL-4)/IL-4 receptor (IL-4R) system in osteoarthritis (OA) we evaluated soluble IL-4R (sIL-4R) levels in sera of patients with different forms of OA and healthy individuals. METHODS: We recruited: 141 patients with hand OA, 70 with nodal and 71 with erosive hand OA; 64 patients undergoing total joint replacement, 34 with hip and 30 with knee OA; and 38 ethnically and geographically age-matched healthy individuals [normal controls (NC)]. RESULTS: Serum sIL-4R concentration was found to be significantly higher in all OA patients than that in NC. When patients were divided into four subgroups (nodal, erosive, hip and knee OA) significant differences were present when comparing NC with each subgroup. This was true also when small-joint OA groups were compared with large-joint OA groups, the latter being associated with higher IL-4R levels. CONCLUSIONS: We found increased levels of sIL-4R in OA patients compared with healthy individuals. We speculate that this reduces availability of IL-4, and its effects on chondrocytes.     

Increased urinary excretion of interleukin-17 in nephrotic patients

BACKGROUND/AIM: Interleukin (IL)-17 is a newly discovered cytokine that is secreted by activated memory CD4+ T cells and modulated the early stage of immune response. To elucidate the pathophysiology of minimal-change nephrotic syndrome (MCNS), we focused on IL-17, which is one of the key factors in regulating an inflammatory response, and thus determined the daily excretion of IL-17 in urine. METHODS: For this purpose, excretion levels of IL-17 were measured in the urine of patients with MCNS during relapse and remission using a highly sensitive sandwich enzyme-linked immunosorbent assay. The data obtained were compared with levels of daily urinary excretion of IL-17 in patients with IgA nephropathy (IgAN). A group of healthy subjects served as control. In both experimental groups urine levels of IL-17 excretion were plotted against their daily urinary protein excretion. RESULTS: We demonstrated increased levels of IL-17 excretion in the urine of patients with MCNS and IgAN as compared to the non-nephrotic and healthy controls. In MCNS the daily urinary IL-17 (uIL-17) excretion was increased and returned to baseline with remission of the nephrotic syndrome (NS). We also demonstrated a positive correlation between urinary protein excretion and daily uIL-17 excretion. CONCLUSION: Taken together, these data indicate that uIL-17 excretion is increased during the NS, suggesting the possibility that daily uIL-17 excretion may reflect the disease activity of NS.     

Polymeric albumin in the urine of patients with nephrotic syndrome.

Dimer and polymer albumin was detected in the urine of a proportion of pantients with a nephrotic syndrome. Most of it was present as S-S bonded dimer and polymer; co-polymers, however, with IgG and alpha (1) anti-trypsin could be demonstrated. It is suggested that albumin polymerizes after it has passed the glomerular membrane. Albumin dimer was associated mainly with minimal change disease and early membranous glomerulopathy in patients, who in general responded well to therapy.     

Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma

PURPOSE: Specific cytokines have been found to be secreted by and influence the growth of prostate cancers in cell culture. Interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), granulocyte macrophage-colony stimulating factor (GM-CSF) and transforming growth factor-beta1 (TGF-beta1) have all been closely associated with prostate cancer. We analyzed the levels of these cytokines in the systemic circulation of patients with varying stages of prostate cancer compared to controls. MATERIALS AND METHODS: Serum IL-6, TNFalpha and GM-CSF were measured using commercially available enzyme linked immunosorbent assays in 5 groups of patients, including controls-19 men presenting to prostate cancer screening with normal digital rectal examination and serum prostate specific antigen (PSA) no greater than 2.0 ng./ml., stage pT2-19 with cancer confined to the prostate in the radical prostatectomy specimen, stage pT3-10 with extraprostatic extension and/or seminal vesicle involvement, stage N1-12 with lymph node metastases at pelvic lymph node dissection, and stage M1-9 with bone metastases. Platelet poor plasma TGF-beta1 was measured using a commercially available enzyme linked immunosorbent assay in controls and patients with stage M1 disease only because it was not available for patients with stages pT2, pT3 and N1 disease. No patient had a history of any other malignancy. All blood specimens were collected before surgery and/or androgen ablation. Statistical analysis was done with the Kruskal-Wallis analysis of variance. RESULTS: Serum IL-6 and platelet poor plasma TGF-beta1 were significantly elevated in patients with clinically evident metastases (p = 0.0008 and 0.0412, respectively) while serum GM-CSF and TNFalpha were not. IL-6 and TGF-beta1 correlated with increasing serum PSA (p = 0.0335 and 0.0386, respectively). GM-CSF did not correlate with PSA or age. In multivariate analysis TNFalpha correlated with age but not PSA. CONCLUSIONS: IL-6 and TGF-beta1 correlate with tumor burden as assessed by serum PSA or clinically evident metastases. Further research is needed to determine the response to androgen ablation as well as the source(s) and actions of these cytokines.     

Significance of high levels of heparin cofactor II in the plasma and urine of adult patients with nephrotic syndrome.

Heparin cofactor II (HCII) is a thrombin inhibitor in human plasma which displays similarities with antithrombin III (ATIII). Hereditary HCII deficiency was recently reported to be associated with thrombophilia. Since thromboembolism constitutes one of the main complications of the nephrotic syndrome (NS), both activities and antigen concentrations of HCII and ATIII were measured in the plasma and urine of 33 adult patients with nephrotic syndrome. The mean HCII plasma level was significantly increased whereas the ATIII level was decreased. Plasma HCII was significantly correlated with proteinuria and with the fibrinogen level, suggesting that HCII could act as an acute phase reactant in patients with NS. HCII antigen was detectable in 16 of the 24 available urine samples, whereas ATIII antigen was present in all of them. In addition, functionally active HCII was detected in most of the urine samples containing HCII antigen, while ATIII was only present in the inactive form. In conclusion, these findings suggest that HCII is submitted to a metabolic pathway different from that of ATIII in patients with NS.     

Elevated serum and urine sialic acid levels in renal diseases of childhood

Serum and urine sialic acid levels were measured in various renal diseases of childhood. Serum sialic acid levels were found to be elevated in patients with idiopathic nephrotic syndrome (INS) at onsets and relapses, acute poststreptococcal glomerulonephritis (PSGN) and chronic glomerulonephritis (CGN) found by chance proteinuria and/or hematuria. A large amount of bound sialic acids were excreted in the urine in INS at onsets and relapses, although the serum sialic acid levels were increased. Sephadex G-200 column chromatography revealed three separate peaks with sialoglycoproteins in a patient with INS at onset, but only two peaks in a normal control subject. These results suggest that some sialoglycoproteins are involved in the development of INS, PSGN and CGN.     

Elevated urine levels of heparin-binding protein in children with urinary tract infection

Background

Urinary tract infection (UTI) is a common infection diagnosis in children, and efficient diagnosis and treatment are important to avoid serious complications. In this study we investigated whether urinary levels of neutrophil-derived heparin-binding protein (HBP) can be used as a marker of UTI in children. These results were compared to those of dipstick analysis, interleukin-6 (IL-6) analysis in urine, and bacterial culturing.

Methods

Seventy-eight children aged 0–18?years with fever and/or symptoms indicating UTI were enrolled in a prospective consecutive study. Urine samples were cultured and analyzed with dipstick, and concentrations of HBP and IL-6 were measured.

Results

Fifteen patients were classified as having UTI, 30 patients had fever but were diagnosed with a non-urinary tract infection, and 33 patients had neither UTI nor fever. Using a urine HBP (U-HBP) cut-off level of 32?ng/mL, the sensitivity and specificity for detecting UTI were 93.3 and 90.3 %, respectively. Receiver operating characteristic curves demonstrated that U-HBP levels were a higher specificity indicator of UTI than urine white blood cell counts or urine IL-6 levels; they also showed a higher sensitivity than the results of the urine nitrite test. All patients with significant growth of clinically relevant bacteria had elevated U-HBP levels.

Conclusion

The results indicate that rapid analysis of U-HBP can provide helpful guidance in the management of children with suspected UTI.     

Elevated levels of serum interleukin-6 are associated with low grade cellular rejection in patients with heart transplantation

Endomyocardial biopsy is the gold-standard procedure to diagnose acute cellular rejection after heart transplantation. This study assessed whether the blood levels of cytokines involved in inflammation and immune activation are useful to detect the presence of acute cellular rejection.MethodsBlood specimens collected before 275 endomyocardial biopsies in 66 patients were assayed for levels of TNFα, IL6, IL1β, and IL2 receptor. The biopsies were grouped according to the presence (n = 41) or absence (n = 234) of acute cellular rejection grade ≥3A of the International Society for Heart and Lung Transplantation. We compared the levels of cytokines in the two groups.ResultsCirculating IL6 levels were significantly higher when there was a low grade (0–2) cellular rejection in the biopsy versus the group of biopsies grade ≥3A (19.8 ± 27 versus 12.9 ± 10 pg/mL; P = .001). An IL6 level higher than 30 pg/mL showed a negative predictive value of 95% for the presence of acute rejection grade ≥ 3A.ConclusionIn heart transplant patients, high levels of serum IL6 were associated with low grade cellular rejection. Determination of IL6 levels may be useful to reduce the number of endomyocardial biopsies during follow-up in these patients.     

Higher plasma interleukin-18 levels associated with poor quality of sleep in peritoneal dialysis patients.

BACKGROUND: Sleep disorders are prevalent in patients with end-stage renal disease. Increasing evidence suggests that cytokines are involved in the regulation of sleep and wakefulness. The purpose of this study was to examine the relationship between quality of sleep and plasma interleukin-18 levels in peritoneal dialysis patients. METHODS: Plasma interleukin-18 levels were determined by the enzyme-linked immunosorbent assay (ELISA) methodology in 57 peritoneal dialysis patients. Quality of sleep was measured using the Pittsburgh Sleep Quality Index. Demographic and routine laboratory data were recorded. RESULTS: In our cohort, the poor sleepers had higher plasma interleukin-18 levels (559.16 +/- 261.22 pg/ml vs 397.49 +/- 191.81 pg/ml, P = 0.01). The plasma interleukin-18 level was positively correlated with the Pittsburgh Sleep Quality Index score (r = 0.286, P = 0.031), that is, there was a positive association between higher plasma interleukin-18 levels and poorer quality of sleep. CONCLUSION: This study demonstrates that interleukin-18 may be involved in sleep disorders in end-stage renal disease patients. Higher plasma interleukin-18 levels are associated with poorer quality of sleep in peritoneal dialysis patients. Whether a cause-and-effect relationship exists between interleukin-18 and quality of sleep deserves further study.     

Interleukin-6 and interleukin-8 levels in the urine of children with renal scarring

Background

Acute pyelonephritis (APN) is one of the most significant bacterial infections in infancy and early childhood, and can lead to permanent kidney damage and chronic renal failure.

Objective

To evaluate interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in the urine of children with renal scarring (RS), searching for clinical information about the immuno-inflammatory process that contributes to RS.

Methods

Urine concentrations of IL-6 and IL-8 were evaluated in 50 children, 33 with RS detected after an episode of acute pyelonephritis (group A) and 17 children with a history of acute pyelonephritis, but without RS (group B). These children were divided into four groups: groupA₁, 23 children with RS and vesicoureteral reflux (VUR); groupA₂, 10 children with RS without VUR; group B₁, 13 children without RS and without VUR; group B₂, 4 children without RS, but with VUR. None of them had had urinary tract infection for a minimum of 6 months. To avoid dilution effects, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg).

Results

Urinary IL-8 levels were below the lower detection limit in all samples. IL-6 was detectable in the majority of children with RS and below the detection limits in the urine samples of children without RS. There were no statistically significant differences between urinary interleukin-6 levels in children with and those without VUR. There was a significant relationship between the grade of renal scars, the time passed since the last episode of acute pyelonephritis and the urinary levels of IL-6 (p?p?Conclusion Further experimental studies are required to demonstrate the correlation between histopathology and urinary cytokine levels.     

环孢素A与他克莫司对大鼠白细胞介素18及白细胞介素10含量的影响

目的检测环孢素A(CsA)与他克莫司(FK506)对大鼠血清及脾组织悬液中白细胞介素18(IL-18)及IL-10含量的影响,探讨CsA和FK506抗排斥反应的不同作用机理。方法将60只Wistar大鼠随机分为3组(每组20只):(1)CsA组:以CsA灌胃(30mg·kg-1·d-1);(2)FK506组:以FK506灌胃(0.6mg·kg-1·d-1);(3)对照组:以生理盐水灌胃(3ml·kg-1·d-1)。用全自动生化分析仪检测肝、肾功能,用酶联免疫吸附试验双抗体夹心法测定大鼠外周血及脾组织悬液中IL-18及IL-10的含量。结果FK506组大鼠血清及脾组织悬液中IL-10含量较对照组明显升高,差异有统计学意义(P<0.05),IL-18与对照组比较明显降低,差异有统计学意义(P<0.05);CsA组血清及脾组织悬液中IL-18明显低于对照组(P<0.05),而IL-10与对照组的差异无统计学意义(P>0.05)。结论FK506可使血清及脾组织悬液中IL-10含量升高,这可能是FK506与CsA抗排斥反应机理不同点之一。     

Involvement of interleukin-18 in patients on maintenance haemodialysis

Maintenance dialysis induces a clinical state of immunodeficiency. The pathway of circulating T cells from haemodialyzed patients is changed and characterized by an increase of Th1 cells. The unbalanced T helper differentiation derives from an altered regulation of interleukin-12 (IL-12), which represents an important inducer of Th1. IL-18 is a pro-inflammatory cytokine expressed by a variety of cell types that is structurally related to the Th1 family and shares biological properties with IL-12 as the promotion of Th1 responses. To explain the involvement of IL-18 in the typical disorders of dialysis, we analyzed IL-18 serum levels in a group of haemodialyzed patients. We enrolled 16 patients on chronic haemodialysis (HD) treatment for end-stage renal failure and 16 healthy volunteers as the control group. IL-18 levels were assessed by immunoenzymatic methods (detection limit was <12.5 pg/ml). HD patients strongly showed higher IL-18 serum levels compared to healthy donors (508.47 +/- 314.39 vs. 193.44 +/- 56.33 pg/ml, p < 0.005). Moreover, IL-18 levels in HD directly correlated to dialytic age (Rho = 0.544, p = 0.0419) and indirectly to Kt/V (Rho = 0.703, p = 0.0086). Our data represent the first evidence of the relation between IL-18 serum levels and HD. In the light of our results, we think that the unbalanced T helper differentiation may depend, at least in part, on an abnormality in the IL-18 production.     

Elevated serum levels of C-reactive protein in hemodialysis patients

Serum C-reactive protein (CRP) levels were measured by nephelometry in 30 healthy subjects (controls) and in 99 patients with uncomplicated terminal uremia on conservative therapy (group 1, n = 30) or chronic hemodialysis (group 2, n = 69). Whereas there was no difference between controls and group 1, both the mean concentration of CRP and the incidence of elevated levels were significantly higher in group 2 in comparison with both controls and group 1. Moreover, the degree of increase in these patients was directly correlated with the duration of hemodialysis. The abnormality, therefore, is somehow related to chronic hemodialysis per se. From a practical standpoint, we concluded that this test cannot be recommended as an acute-phase reactant in this clinical setting.