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      Relationships of Urinary VEGF/CR and IL-6/CR with Glomerular Pathological Injury in Asymptomatic Hematuria Patients

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          Abstract

          Background

          Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) have important functions in injury and repair processes of glomerular intrinsic cells. A study was conducted to analyze the urinary VEGF/creatinine (CR) and IL-6/CR levels in simple hematuria patients after excluding the interference of creatinine. We aimed to investigate the function and relationships of the above indices in the glomerular pathological injury process, and to elaborate the values of urinary VEGF and IL-6 changes in the diagnosis of asymptomatic hematuria or hematuria with proteinuria.

          Material/Methods

          A total of 121 renal hematuria patients diagnosed by clinical and laboratory tests were included as research subjects. The midstream fresh morning urine was collected on the day renal biopsy was performed.

          Results

          The IL-6/CR value of the group III was significantly greater than in group I (Z=−2.478, P<0.05), with a statistically significant difference between these 2 groups. The VEGF/CR value of group III was significantly greater than in group II ( P<0.01). Compared with group I, the VEGF/CR of group III was significantly greater (Z=−4.65, P<0.01), with a statistically significant difference.

          Conclusions

          The VEGF/CR and IL-6/CR values in simple hematuria patients were positively correlated with glomerular pathological injury scores. VEGF/CR and IL-6/CR might be used as biological diagnostic indicators in determining the extent of simple hematuria glomerular injury.

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          Most cited references21

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          Maladaptive role of IL-6 in ischemic acute renal failure.

          The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.
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            Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties.

            Normal glomerular filtration depends on the combined properties of the three layers of glomerular capillary wall: glomerular endothelial cells (GEnC), basement membrane, and podocytes. Podocytes produce endothelial factors, including angiopoietin 1 (ang1), and vascular endothelial growth factor (VEGF), whereas GEnC express their respective receptors Tie2 and VEGFR2 in vivo. As ang1 acts to maintain the endothelium in other vascular beds, regulating some actions of VEGF, these observations suggest a mechanism whereby podocytes may direct the unique properties of the glomerular endothelium. This interaction was investigated by studies on the barrier properties of human GEnC in vitro. GEnC were examined for expression of endothelium-specific markers by immunofluorescence and Western blotting and for typical responses to TNF-alpha by a cell-based immunoassay. Expression of angiopoietin and VEGF receptors was examined similarly. Barrier properties of GEnC monolayers cultured on porous supports were investigated by measurement of transendothelial electrical resistance (TEER) and passage of labeled albumin. Responses to a cAMP analogue and thrombin were examined before those to ang1 and VEGF. Results confirmed the endothelial origin of GEnC and their expression of Tie2 and VEGFR2. GEnC formed monolayers with a mean TEER of 30 to 40 Omega/cm(2). The cAMP analogue and thrombin increased and decreased TEER by 34.4 and 14.8 Omega/cm(2), respectively, with corresponding effects on protein passage. Ang1 increased TEER by 11.4 Omega/cm(2) and reduced protein passage by 45.2%, whereas VEGF reduced TEER by 12.5 Omega/cm(2) but had no effect on protein passage. Both ang1 and VEGF modulate GEnC barrier properties, consistent with potential in vivo roles; ang1 stabilizing the endothelium and resisting angiogenesis while VEGF induces the high permeability to water, characteristic of the glomerular endothelium.
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              Asymptomatic isolated microscopic haematuria: long-term follow-up.

              Evidence to support current diagnostic and management approaches to asymptomatic haematuria is lacking and based on short-term clinical observation. To ascertain the natural history and long-term outcome of asymptomatic and isolated haematuria, and to determine the clinical correlates of adverse renal events. Prospective observational referral-based study. We evaluated 90 consecutive patients with isolated microscopic haematuria, first seen between 1985 and 1996 at an out-patient nephrology clinic. We defined adverse renal events as the development of proteinuria (> 0.5 g/24 h) on two consecutive occasions, development of hypertension, or impaired renal function characterized by glomerular filtration rate (GFR) of <60 ml/min/1.73 m(2) for 3 months or more. There were 24 males and 66 females, median follow-up 5.2 years (total 442 patient-years). Mean age at presentation was 39 +/- 13 years. Fifteen (17%) had complete resolution of microscopic haematuria. One (1%) had transitional cell carcinoma of urinary bladder 20 months after initial presentation. Twelve (13%) developed hypertension, and 10 (11%) proteinuria. Only one developed chronic renal failure, 2.3 years after initial presentation. Altogether, 16 (19%) developed at least one adverse event, after a mean 42 months. Neither history of renal biopsy nor histological diagnosis of glomerular disease was predictive of renal events. Three independent variables were predictive of adverse renal events: baseline proteinuria (RR per 0.1 g/day 2.04; 95%CI 1.13-3.68; p = 0.018); MDRD-estimated GFR at presentation (RR per 10 ml/min/1.73 m(2) decrement 2.01; 95%CI 1.09-3.71; p = 0.025); and baseline serum urate (RR per 100 micromol/l 1.02; 95%CI 1.01-1.03; p = 0.009). Asymptomatic microscopic haematuria can lead to adverse renal events, and warrants nephrologist evaluation and regular follow-up. Its isolated microscopic haematuria is closely related to early hints of chronic kidney disease, such as low-grade proteinuria and renal insufficiency, as well as hyperuricaemia.
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                Author and article information

                Journal
                Med Sci Monit
                Med. Sci. Monit
                Medical Science Monitor
                Medical Science Monitor : International Medical Journal of Experimental and Clinical Research
                International Scientific Literature, Inc.
                1234-1010
                1643-3750
                2015
                30 January 2015
                : 21
                : 356-362
                Affiliations
                Integrated Chinese and Western Medicine Treatment of Renal Disease Centre, Beidaihe Sanatorium of Beijing Military Area Command, Chinese PLA, Qinhuangdao, China
                Author notes
                Corresponding Author: Minghui Song, e-mail: minghuisongcn@ 123456163.com
                [A]

                Study Design

                [B]

                Data Collection

                [C]

                Statistical Analysis

                [D]

                Data Interpretation

                [E]

                Manuscript Preparation

                [F]

                Literature Search

                [G]

                Funds Collection

                [*]

                Co-first author: Lu Ma, Yinghe Gao

                Article
                892085
                10.12659/MSM.892085
                4321409
                25634015
                d5152f5d-6ce2-4b92-8ccf-65d85c0327d0
                © Med Sci Monit, 2015

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License

                History
                : 25 July 2014
                : 25 September 2014
                Categories
                Clinical Research

                cytokine receptor gp130,kidney glomerulus,vascular endothelial growth factor a,hematuria

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