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Background/Aims: Angiotensin II (AngII) is pivotal in the pathogenesis of progressive kidney disease. We have recently shown that AngII induced an increase in markers of oxidative stress, adaptive responses and upregulated stress-related gene expression in immortalised human proximal tubular (HK-2) cells. However, these observed effects of AngII were not mediated solely via AngII type 1 receptor (ATR1). Both HK-2 cells and primary human renal proximal tubular cells (RPTEC) are useful tools to investigate the renin-angiotensin system (RAS), but data on the local expression of the RAS in these cells remain limited. We therefore characterised RAS expression in RPTEC and HK-2 cells. Methods: The mRNA and protein expression of RAS in RPTEC and HK-2 cells was examined by RT-PCR, Western blotting and immunoprecipitation. Results: In both cell lines, mRNA for angiotensin-converting enzyme (ACE) and mRNA and protein expression for angiotensinogen, renin, ACE2, ATR1 and ATR4 were detected. Candesartan, a specific ATR1 blocker, effectively blocked the expression of 80% of the stress-related genes that were upregulated in HK-2 cells following exposure to AngII. Con clusion: These data support a role for AngII in mediating oxidative stress via other receptor types stimulated by AngII and confirm that it is possible to investigate ATR4 pathways of potential injury in RPTEC. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The high morbidity and mortality rates in hemodialysis (HD) patients are due, at least in part, to their increased risk for cardiovascular diseases (CVD). This prospective study evaluated the effect of growth hormone (GH) on a number of CVD risk markers in adult patients on HD. Methods: 139 HD patients were randomized to one of three GH doses or to placebo. Change from baseline in lean body mass (LBM), CVD risk markers (e.g. lipid profile, plasma homocysteine, inflammatory markers, blood pressure, IGF-I, IGFBP-3 and echocardiography) and correlations with serum IGF-I levels and body mass index were evaluated. Results: LBM increased in GH-treated groups compared with placebo (p < 0.001 pooled GH groups vs. placebo). IGF-I (p = 0.0027) and serum high-density-lipoprotein cholesterol levels (p = 0.038) increased with GH treatment. Serum low-density-lipoprotein cholesterol showed a trend to reduction. IGF-I was negatively correlated with plasma homocysteine levels (p = 0.01) and systolic blood pressure (p < 0.0001). Logistic regression analysis showed that interleukin-6, ghrelin and hematocrit values were significant determinants of all-cause mortality. Left ventricular mass was unchanged from baseline in GH-treated groups. Conclusion: In adult HD patients, GH treatment had a predominantly beneficial effect on CVD risk markers. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Proteinuria is pathogenic to proximal tubular cells (PTC) and linked with progression to renal failure. The aim of this study was to determine the effects of human serum albumin (HSA) overload on the changes in gene and protein expression stimulated by oxidative stress in PTC and any interaction with ANG II that is pivotal in disease pathogenesis. Markers of oxidative stress, antioxidant defences, transcription factor activation, and the expression of stress-related genes were measured in human PTC (HK-2 cells) overloaded with either globulin-free fatty acid free (GF/FAF) HSA or globulin-free (GF) HSA. The effects of ANG II were also determined. HSA overload in HK-2 cells caused PTC hyperfunction, increased oxidative stress, and an upregulation of adaptive responses and stress-related genes. Some responses were common to both HSAs but others were unique to either HSA and unaffected by addition of ANG II or candesartan (a specific ANG II type 1 receptor blocker). ANG II also independently induced oxidative stress and upregulated other stress-related genes. HSA overload in HK-2 cells stimulated increased oxidative stress and upregulated changes in stress-related gene expression indicating new pathways of PTC injury that are not mediated via ANG II type I receptors. [ABSTRACT FROM AUTHOR]

This analysis was performed to define the incidence of pretransplant microbial contamination of donor kidneys, and to assess the resultant morbidity including infections requiring therapy, and graft loss. Case records of all 638 renal allograft recipients patients transplanted in our centre during the period June 1990 to October 2000 were studied. All the recipients were given a single dose of intravenous antibiotics at the time of induction of anaesthesia. A total of 775 microbiology reports on perfusion fluid, kidney swabs and ureteric tissue were retrieved. Fifty-eight of 638 (9.1%) patients were transplanted with a graft that showed preoperative contamination. 18 of these 58 patients (31%) subsequently required antibiotic treatment. Thirty of 32 patients who received kidney contaminated with skin flora had a benign course (i.e. no unexplained, no positive blood cultures or graft infection). By contrast, seven of nine recipients with grafts whose perfusion fluid yielded lactose fermenting coliforms (LFCs) required antibiotics and three of nine of them suffered graft loss as a result. Two of these patients had bacteraemia caused by LFC, and one died. Three of five patients with positive cultures due to yeast required treatment with antifungals. None of the four patients who had graft contaminated byStaphylococcus aureusbecame infected. One-year 49/58 (85%) of these patients survived with functioning graft. Overall 1-year patient survival was 53/55 (92%). These data suggest that contamination of renal allografts by LFCs or yeasts need to be treated preemptively before the onset of clinical manifestations. By contrast, contamination with skin contaminants does not pose a risk to the graft. [ABSTRACT FROM AUTHOR]

This study aims to explore the utility of serial duplex scanning and to compare its results with those of single time-point scans of renal allografts in the diagnosis of acute rejection (AR). A retrospective analysis of 6017 serial duplex scans (mean: 9.8 scans per patient, 5.7 of which were done during the first 10 days) was performed in 614 patients with 462 episodes of AR from 1992-2000. Even in the absence of AR (n = 278), there were day-to-day fluctuations in pulsatility index (PI) and resistive index (RI). An increase of > 10% in intra-renal indices was noted 0.95 days (mean) before the commencement of treatment for AR (SD 1.3, range 1-6 days). In patients with acute tubular necrosis (ATN), who have high base line indices, sensitivity of single value of PI and RI was 58% (cut-off level 1.8) and 68% (cut-off level 0.8), with specificity of 66% and 56%, respectively. By contrast, a > 10% increase over the previous 'best' in PI and RI had a sensitivity of 78% and 60% respectively, and a specificity of 78% and 90%, respectively. Reversal of flow during diastole (n = 50) was found to be associated with 22% graft loss within 3 months of transplantation. We can conclude that a considerable overlap between the indices of patients with AR and those with ATN greatly limits the diagnostic yield of duplex scanning. Nonetheless, serial scanning of renal allografts is more likely to herald the need for biopsy in the diagnosis of AR than one-time scanning. [ABSTRACT FROM AUTHOR]

Chronic vascular rejection (CR) is the commonest cause of renal transplant loss, with few clues to etiology, but proteinuria is a common feature. In diseased native kidneys, proteinuria and progression to failure are linked. We proposed a pathogenic role for this excess protein at a tubular level in kidney diseases of dissimilar origin. We demonstrated in both nephrotic patients with normal function and in those with failing kidneys increased renal tubular catabolisman and turnover rates of a peptide marker, Aprotinin (Apr), linked to increased ammonia excretion and tubular injury. These potentially injurious processes were suppressed by reducing proteinuria with Lisinopril. Do similar mechanisms of renal injury and such a linkage also occur in proteinuric transplanted patients with CR, and if so, is Lisinopril then of beneficial value? We now examine these aspects in 11 patients with moderate/severe renal impairment (51CrEDTA clearance 26.2 ± 3.3 mL/min/1.73m2), proteinuria (6.1 ± 1.5 g/24 h) and biopsy proven CR. Lisinopril (10–40 mg) was given daily for 2 months in 7 patients. Four others were given oral sodium bicarbonate (Na HCO3) for 2 months before adding Lisinopril. Renal tubular catabolism of intravenous 99mTc-Apr (Apr* 0.5 mg, 80 MBq), was measured before and after Lisinopril by γ-ray renal imaging and urinary radioactivity of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Total 24 h urinary N-acetyl-β-glucoaminidase (NAG) and ammonia excretion in fresh timed urine collections were also measured every two weeks from two months before treatment. After Lisinopril proteinuria fell significantly (from 7.8 ± 2.2 to 3.4 ± 1.9 g/24 h, p < 0.05). This was associated with a reduction in metabolism of Apr* over 26 h (from 0.5 ± 0.05 to 0.3 ± 0.005% dose/h, p < 0.02), and in fractional degradation (from 0.04 ± 0.009 to 0.02 ± 0.005/h, p <0.01). Urinary ammonia fell,... [ABSTRACT FROM AUTHOR]

Chronic metabolic acidosis occurs commonly in chronic renal failure (CRF). The proximal renal tubular cell is the site in the kidney of high oxidative metabolic activity and in CRF is associated with adaptive hypertrophy and hypermetabolism. We hypothesised that chronic acidosis may lead to increased generation of reactive oxygen species due to increased oxidative activity. We developed a novel model of chronic acidosis in LLC-PK1 cells and measured markers of oxidative stress and metabolism. Acidosis led to a reduction in cellular total glutathione and protein thiol content and an increase in glutathione peroxidase activity and NH[sub 3] generation. The expression of constitutively expressed heat stress protein (HSP) HSC70 and HSP60 increased at pH 7.0.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]