Urinary Transforming Growth Factor Beta Research Articles

Role of Urinary Transforming Growth Factor Beta-B1 and Monocyte Chemotactic Protein-1 as Prognostic Biomarkers in Posterior Urethral Valve.

Background:Posterior Urethral Valves (PUV) are the most common cause of congenital LUT obstruction in males. Biomarkers of glomerular or tubular injury may be of particular value in predicting the need for surgical intervention or in tracing progression of chronic kidney disease. Measurement of biomarker in urine is relatively easy.Aim:To evaluate the changes in values of urinary Transforming Growth Factor Beta 1(TGF-B1) and Monocyte Chemotactic Protein (MCP-1) before and after valve ablation and its prognostic value in Posterior urethral valve.Material and Method:This prospective study was conducted from September 2016 to August 2018. The study group included 20 consecutive male babies with the diagnosis of PUV treated and followed up versus equal numbers of age matched control without any renal or urinary tract disease. Pre-operative urine samples were collected in Operative room. Cystoscopy and valve ablation was done. Follow up was done clinically by urinary stream and radiologically with VCUG. Follow-up was planned at 1 month, 3 months and 6 months following cystoscopic valve ablation. All collected urine samples were centrifuged at 10,000 rpm for 20 minutes. Supernatant was collected and two divided aliquots were stored at -200c to be thawed on the day of assay. Optical density of each well was recorded at 450 nm and 540 nm A p-value of <0.05 was considered to be statistically significant.Result and Discussion:Out of 20 cases of PUV, 14 (70%) cases were 1st born males of their family. The median age at the time of valve ablation in PUV cases was 2.5 (1.20-3.87) years.. Most common symptoms are fever and UTI. The preoperative median serum creatinine level was 1.65 mg/dl(1.22-2.42) pre-ablation, and fall significantly after ablation. Median eGFR level (calculated) was 25.635 (16.38-35.40) and after 6 months was 71.490 (45.44-96.93). Preoperative median MCP1 in PUV cases was 147.2 (82.8-512.5) and significant difference was also found in 1st, 3rd and 6th months after surgery (p<0.001, p=0.004 and p=0.002).Preoperative median TGF-B1 level was 197.8 pg/ml (79.9-386.4). There was no statistically significant change in TGF-B1 level at preoperative to 1 month and preop to 3 months after surgery but at 6 months after surgery the median TGF-B1 level significantly decreased as compared with preoperative TGF-B1 level.Conclusion:TGF β1 and MCP1 can be considered as prognostic urinary biomarkers in patients of PUV and can be used to specify and counsel patient's attendant regarding possibility of ESRD and need for further intervention.

Changes in urinary angiotensinogen posttreatment in pediatric IgA nephropathy patients.

Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues. These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients.

Serum and urinary transforming growth factor beta 1 as biochemical markers in diabetic nephropathy patients

Diabetic nephropathy is a common complication of diabetes mellitus. Transforming growth factor beta 1 (TGF-β1) is considered to be one of the major cytokines involved in the regulation of extracellular matrix (ECM) synthesis and degradation. Discrepant results were reported for urine TGF-β1 in diabetic patients. The aim of the present study is to investigate urine and serum TGF-β1 in patients with type II diabetes with and without nephropathy.The study was performed on 72 patients with type II diabetes (26 macroalbuminuria, 27 microalbuminuria and 19 normoalbuminuria) together with 30 healthy subjects to serve as controls. Urinary and serum TGF-β1 and urine albumin were investigated by Elisa, plasma glucose, whole blood glycated hemoglobin, Urinary and serum total protein, creatinine, were determined by colorimetric methods. Urine and serum TGF-β1 were significantly increased in all diabetic groups being more pronounced in the macroalbuminuria group than micro and normoalbuminuria groups. Also urine total protein was increased, being more pronounced in macroalbuminuria group than other groups. Urinary and serum TGF-β1 showed high positive correlation with urinary total protein concentration in macro and microalbuminuria groups r = (0.9, 0.9, 0.8 and 0.89) respectively. The results revealed significant increase in Urinary and serum TGF-β1 and their concentrations in urine were parallel to urine proteins and albumin concentrations; urinary and serum TGF-β1 showed high positive correlation with urinary total protein, so it could be used as a marker with total protein and albumin to confirm the diabetic nephropathy in type II diabetic patients.

Association of urinary transforming growth factor-β1 with the ureteropelvic junction obstruction.

Background:We aimed to compare the level of urinary transforming growth factor-beta 1 (TGF-β1) in children with ureteropelvic junction obstruction (UPJO) with the normal peers.Materials and Methods:In this case-control study, we enrolled children with UPJO and matched normal peers. Sterile urine was collected from the subjects and urinary TGF-β1 was measured by ELISA method. Also, degree of the UPJO and the magnitude of the renal injury were assessed by ultrasonography and measuring glomerular filtration rate (GFR), respectively. Study variables were then compared between the study groups regarding the level of urinary TGF-β1.Results:A total of 25 children with UPJO (age = 7.4 ± 4.5 years; male = 16) were compared with 25 healthy peers (age = 6.8 ± 5.6 years; male = 16). Mean GFR in the UPJO and the control group were 112.4 ± 10.1 and 123.29 ± 4.4, respectively. Mean urinary TGF-β1 in the UPJO group was 87.1 ± 12.6 pg/ml vs 30.5 ± 14.5 pg/ml in the control group. The level of urinary TGF-β1 was significantly associated with the degree of TGF-β1 and patients with grade IV hydronephrosis had the highest level of urinary TGF-β (P = 0.0001).Conclusion:Based on our findings, biomarkers such as TGF-β1 can successfully be used for confirming UPJO. However, further studies are needed to determine the proper cut point for diagnosis confirmation.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery

BackgroundCardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFβ1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFβ1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFβ1 phenotype as well as renal outcome. MethodsIn 408 elective cardiac surgery patients we measured pre- and 24h post-operative urinary TGFβ-1, IL1ra and TNFsr2 and pre- and 2h post-operative plasma TNFα and IL-10. Post-operative responses were compared for each cytokine in patients grouped according to presence or absence of renal dysfunction defined as a drop from baseline eGFR of greater than 25% (as calculated by the method of modification of diet in renal disease (MDRD)) occurring (1) within the first 24 and (2) 48 postoperative hours (early renal dysfunction), (3) on the fifth postoperative day (late renal dysfunction) or (4) at any time throughout the 5day postoperative period (early and late combined). Patient genotype was determined for TNF/G-308A, TGFβ1-509 C/T, IL10/G-1082A and ACE I/D. ResultsPost-operative plasma IL-10 and urinary TGFβ1 responses were significantly higher in patients who developed early renal dysfunction. IL1ra and TNFsr2 responses were significantly lower 24h post-operatively in patients who developed late renal dysfunction. Genotype did not alter cytokine phenotype or outcome. Conclusions/inferencesCytokine profiling may help predict early and late renal dysfunction. Genotypes studied did not alter phenotype or outcome.

Synergistic therapy of enalapril and Cordyceps sinensis in the improvement of renal function in chronic allograft nephropathy patient

Chronic allograft nephropathy (CAN) still remains an important factor that affects the long-term survival of renal recipients. The aim of the study was to investigate synergistic effect of enalapril (an angiotensin converting enzyme inhibitor, ACEI) and Cordyceps sinensis (Bailing capsule, fermented agent of C. sinensis ) on CAN and pursue an effective therapy to control CAN progression. A total of 84 CAN patients who underwent transplantation (live related donor, no prisoners were used in this study) were involved in the study and randomized into four groups. Group A (n=22) received combined treatment of enalapril (10 mg/day) and C. sinensis (2.0 g/per times, three times per day), group B (n=20) was treated with enalapril (10 mg/day), group C (n=21) with C. sinensis (same dose as in group A) and group D (n=21) treated with immunosuppressive agents was set as control. Serum creatinine (SCr), blood urea nitrogen (BUN), creatinine clearance rate (CCr), urinary protein in 24 h (24 h Upro) and urinary transforming growth factor beta 1 (TGF-s 1 ) of all patients were measured before treatment, and at six months after treatment. After treatment for six months, SCr and CCr were improved while 24 h Upro and urinary TGF-s 1 decreased in group A , and SCr improved and 24 h Upro decreased in group C. Patients of group A obtained the highest degree of improvement, and more patients obtained renal improvement and stability than in the other groups. The results of the study show that combined use of enalapril and C. sinensis takes advantages of reducing excretion of urinary protein, improving renal function and retarding CAN progression for CAN patients compared with single use of enalapril or C. sinensis . Keywords: Chronic allograft nephropathy, renal transplantation, enalapril, Cordyceps sinensis

Assessment of plasma and urinary transforming growth factor beta 1 (TGF-β1) in children with lupus nephritis

Background: Kidney disease is one of the most serious manifestations of systemic lupus erythematosus (SLE). Despite the improvement in the medical care of SLE in the past two decades, the prognosis of lupus nephritis remains unsatisfactory. Transforming growth factor- β1 (TGF-β1) is an immunosuppressive cytokine, as it inhibits T and B cell proliferation and NK cell cytotoxic activity . Objective: The aim of this study was to assess serum and urinary TGF- β1 levels in children with SLE and their possible role in the renal involvement and activity of the disease. Study design: This cross sectional study was conducted in Nephrology Unit of Pediatric Department, plus Outpatient Clinic of Rheumatology Department, Zagazig University Hospital during the year of 2010. Methods: Twenty-five pediatric patients with SLE were randomly selected and classified according to into 2 groups: Group (Ι): included 13 patients presented with urinary abnormalities and/or disturbed renal function(active nephritis): 5 males, 8 females. Their mean age was 9.7±2.53 years and the mean disease duration was 2.46±1.4 years. Group (ΙΙ): included 12 patients presented by lupus without nephritis : 5 males,7 females. Their mean age was 9.9±2.1 years and the mean disease duration was 2.41±0.9 years. Control group(group ΙΙΙ): Twenty healthy children of matched age and sex served as a control group included 8 males ,12 females. Their mean age was 10.0±2.3 years. Results: There was no significant difference among studied patients groups regarding age, sex , disease duration and lupus therapy (p>0.05). There was a significant difference between both groups regarding urinary albumin and serum creatinine (2.76±0.97 and 1.96±0.84 mg/dl respectively), while there was a high significant difference between them regarding C3 (47.3±12.5 and 76.6±6.6 mg/ml respectively) and anti double stranded DNA (anti-dsDNA) (80.7±32.8 and 26.8±4.5 IU/ml respectively). Plasma TGF- β1 showed significantly lower levels in patients with active nephritis relative to other groups, while urinary TGF- β1 levels were significantly high in SLE patients either with active or silent nephritis when compared with the control group. Plasma TGF- β1 showed a highly significant positive correlation with C3 and a highly significant negative correlation with serum creatinine, urinary albumin, anti dsDNA and SLE disease activity index (SLEDAI) score. While, urinary TGF- β1 had a significant negative correlation with C3 and a high significant positive correlation with anti-dsDNA and SLEDAI score. Conclusion: Low plasma TGF β1 level and increased urinary TGF β1 excretion denotes active renal affection in children with SLE. Keywords: SLE , nephritis , TGF- β1 Egypt J Pediatr Allergy Immunol 2011;9(1):21-27

Urinary transforming growth factor beta-1 as a marker of renal dysfunction in sickle cell disease

Renal dysfunction affects 5-18% of patients with sickle cell disease (SCD). To date, no studies have described urinary levels of transforming growth factor β-1 (TGF-β1), a marker of fibrosis, and neutrophil gelatinase-associated lipocalin (NGAL), a marker of acute/chronic kidney disease, as biomarkers in identifying patients at risk of developing renal disease in SCD. We hypothesized that SCD subjects will have increased urinary excretion of TGF-β1 and NGAL compared with healthy controls (CTR). We examined 51 SCD subjects: 42 HbSS, 8 HbSC, and 1 HbSD. Sixteen out of 42 patients with HbSS were on hydroxyurea (HU). Urinary excretion of TGF-β1 was 26.4 ± 1.5 pg/mgCr in SCD subjects vs 15.0 ± 2.4 pg/mgCr in CTR (p<0.00001). SCD patients with hemoglobin < 9 g/dl had higher urinary TGF-β1 than patients with milder anemia (p=0.002). Urinary TGF-β1 trended lower in HbSS patients treated with HU (23.61 ± 2.6 pg/mgCr), vs patients not on HU (27.69 ± 1.8 pg/mgCr; p=0.055). There was no correlation between urinary TGF-β1 and microalbuminuria or estimated glomerular function. There was no difference in urinary NGAL in SCD patients vs CTR. We suggest that urinary TGF-β1 may serve as a marker of early renal injury in SCD.

Intratubular hydrodynamic forces influence tubulointerstitial fibrosis in the kidney

Renal epithelial cells respond to mechanical stimuli with immediate transduction events (e.g. activation of ion channels), intermediate biological responses (e.g. changes in gene expression), and long-term cellular adaptation (e.g. protein expression). Progressive renal disease is characterized by disturbed glomerular hydrodynamics that contributes to glomerulosclerosis, but how intratubular biomechanical forces contribute to tubulointerstital inflammation and fibrosis is poorly understood. In-vivo and in-vitro models of obstructive uropathy demonstrate that tubular stretch induces robust expression of transforming growth factor beta-1, activation of tubular apoptosis, and induction of nuclear factor-kappaB signaling, which contribute to the inflammatory and fibrotic milieu. Nonobstructive structural kidney diseases associated with nephron loss follow a course characterized by compensatory increases of single nephron glomerular filtration rate and tubular flow rate. Resulting increases in tubular fluid shear stress reduce tissue-plasminogen activator and urokinase enzymatic activity, which diminishes breakdown of extracellular matrix. In models of high dietary Na intake, which increases tubular flow, urinary transforming growth factor beta-1 concentrations and renal mitogen-activated protein kinase activity are increased. In conclusion, intratubular biomechanical forces, stretch, and fluid shear stress generate changes in intracellular signaling and gene expression that contribute to the pathobiology of obstructive and nonobstructive kidney disease.

Urinary transforming growth factor beta1 in children and adolescents with congenital solitary kidney

The aim of the study was to assess urinary transforming growth factor beta1 (TGF beta1) level in children and adolescents with congenital solitary kidney (CSK), depending on estimated glomerular filtration rate (eGFR) and compensatory overgrowth of the kidney. The study group (I) consisted of 65 children and young adults, 0.5-22 years of age (median 10.0 years) with CSK and no other urinary defects. The control group (C) contained 44 healthy children and adolescents, 0.25-21 years old (median 10.3 years). We used an enzyme-linked immunosorbent assay (ELISA) to determine the urinary level of TGF beta1, the Jaffe method to assess creatinine concentration, and the Schwartz formula to estimate GFR. Kidney length was measured while the patient was in a supine position, and overgrowth (O%) was calculated with reference to the charts. Urinary TGF beta1 level in CSK patients was more than twice as high as that in controls (P < 0.05). Also, eGFR in patients with CSK exceeded the values in the control group (P < 0.01). Compensatory overgrowth of the solitary kidney was found (median 19.44%). Urinary TGF beta1 concentration was positively correlated with eGFR (r = 0.247, P < 0.05), uric acid concentration (r = 0.333, P < 0.01), and percentage of overgrowth (r = 0.338, P < 0.01) and body mass index (BMI) centile (r = 0.274, P < 0.05). We concluded that, although proteinuria and progressive renal insufficiency is not observed in patients with CSK during childhood, the renal haemodynamic changes are present and may be a risk factor for impairment of renal function and hypertension in future life.

Effect of Lepidium sativum L. on renal glucose reabsorption and urinary TGF‐β1 levels in diabetic rats

The purpose of this study was to determine the mechanism underlying the hypoglycaemic activity of the aqueous extract perfusion of Lepidium sativum L. (LS) in normal and streptozotocin-induced diabetic rats. The aqueous LS extract was administered intravenously and the blood glucose levels were determined within 4 h of treatment. Plasma insulin concentrations and glycosuria were determined. The 24 h urinary transforming growth factor-beta1 (ELISA) was evaluated in diabetic and control rats 15 days after oral treatment with the aqueous LS extract at a dose of 20 mg/kg. The study showed that LS at a dose of 10 mg/kg/h reduced blood glucose levels both in normal and diabetic rats (p < 0.001). At the same time as a potent increase of glycosuria was observed both in normal and diabetic rats (p < 0.001). In addition, oral administration of LS for 15 days normalized glycaemia (p < 0.001), enhanced glycosuria (p < 0.05 vs diabetic control) and decreased the amount of urinary TGF-beta1 (p < 0.01) in diabetic rats. It is concluded that the aqueous LS extract caused a potent inhibition of renal glucose reabsorption which in turn reduced blood sugar. This renal effect is at least one mechanism explaining the observed hypoglycaemic activity of this plant in normal and diabetic rats.

The diagnostic efficacy of urinary TGF-β1 and VEGF in bladder cancer: Comparison with voided urine cytology

The purpose of this study was to evaluate the diagnostic efficacy of urinary transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor (VEGF) in comparison with voided urine cytology in the detection of bladder cancer. This study included 120 patients with bladder cancer, 54 patients with benign urological disorders and 55 healthy volunteers. Urine supernatant was used for estimation of TGF-beta1 and VEGF by ELISA. VEGF was detected by Western blot (WB) analysis in the urine supernatant of randomly selected bladder cancer patients. The urine sediment was used for cytology. There was a statistically significant difference in the median levels of TGF-beta1 (P=0.002) and VEGF (P=0.000) between the control, benign and malignant groups. The concordance rate of VEGF ELISA with VEGF WB was 96.3%. The overall sensitivity and specificity were 70.8% and 90.8% for voided urine cytology, 71.6% and 59.6% for TGF-beta1, and 76.7% and 61.5% for VEGF. The combined use of voided urine cytology with TGF-beta1 and VEGF improved the sensitivity up to 94.9%, although it lowered specificity to 62.0%. There was a significant association between positivity rate of TGF-beta1 and positive urine cytology samples (P=0.023). Median level and positivity rate of VEGF were significantly associated with early stage (I, II) of bladder carcinoma (P=0.01 and 0.025, respectively). Our data indicate that urinary TGF-beta1 and VEGF had higher sensitivities compared to voided urine cytology. Moreover, the combined sensitivity of voided urine cytology with TGF-beta1 and VEGF together was higher than sensitivity of voided urine cytology alone in detection of bladder cancer.

The Effect of Mild Hyperuricemia on Urinary Transforming Growth Factor Beta and the Progression of Chronic Kidney Disease

Although mild hyperuricemia is common in patients with renal disease, it has usually been considered a marker of reduced nephron mass rather than a risk factor for progression of kidney disease. On the other hand, experiments in a rat model demonstrated important deleterious effects of mild hyperuricemia on several aspects of renal structure and function. In the present investigation, the impact of the discontinuation of allopurinol therapy on the control of hypertension and the rate of progression of chronic kidney disease was considered. The present work involved 50 patients, suffering from stage 3 and 4 chronic kidney disease. All of them were on chronic allopurinol therapy for the treatment of mild hyperuricemia. Their blood pressure, serum creatinine and uric acid levels were followed for 12 months following allopurinol withdrawal. Urinary transforming growth factor beta-1 (TGF-β₁) was assayed by a solid-phase enzyme-linked immunosorbent assay. After allopurinol withdrawal, significant worsening of hypertension, significant acceleration of the rate of loss of kidney function and a significant increase in the urinary excretion of TGF-β₁ were observed in the group of patients who were not receiving pharmacological blockers of the renin-angiotensin system. In conclusion, asymptomatic hyperuricemia has a deleterious effect on the progression of chronic kidney disease and the control of hypertension. This effect was blocked by treatment with renin-angiotensin system blockers.

Urinary Transforming Growth Factor-beta 1 as a marker of response to immunosuppressive treatment, in patients with crescentic nephritis.

BackgroundCrescentic nephritis is characterized by formation of cellular crescents that soon become fibrotic and result in irreversible damage, unless an effective immunosuppressive therapy is rapidly commenced. TGF-β1 is involved in the development of crescents through various pathways. The aim of this study was to identify whether the determination of urinary TGF-β1 levels in patients with crescentic nephritis could be used as a marker of response to treatment.MethodsFifteen patients with crescentic nephritis were included in the study. The renal expression of TGF-β1 was estimated in biopsy sections by immunohistochemistry and urinary TGF-β1 levels were determined by quantitative sandwich enzyme immunoassay (EIA). TGF-β1 levels were determined at the time of renal biopsy, before the initiation of immunosuppressive treatment (corticosteroids, cyclophosphamide and plasma exchange). Twelve patients with other types of proliferative glomerulonephritis and ten healthy subjects were used as controls.ResultsImprovement of renal function with immunosuppressive therapy was observed in 6 and stabilization in 4 patients (serum creatinine from 3.2 ± 1.5 to 1.4 ± 0.1 mg/dl and from 4.4 ± 1.2 to 4.1 ± 0.6 mg/dl, respectively). In 5 patients, with severe impairment of renal function who started on dialysis, no improvement was noted. The main histological feature differentiating these 5 patients from others with improved or stabilized renal function was the percentage patients with poor response to treatment were the percentage of glomeruli with crescents and the presence of ruptured Bowman's capsule and glomerular necrosis. Urinary TGF-β1 levels were significantly higher in patients who showed no improvement of renal function with immunosuppressive therapy (930 ± 126 ng/24 h vs. 376 ± 84 ng/24 h, p < 0.01). TGF-β1 was identified in crescents and tubular epithelial cells, whereas a significant correlation of TGF-β1 immunostaining with the presence of fibrocellular cresents was observed (r = 0.531, p < 0,05).ConclusionIncreased TGF-β1 renal expression and urinary excretion that is related to the response to immunosuppressive therapy was observed in patients with crescentic nephritis. Evaluation of urinary TGF-β1 levels may be proved a useful marker of clinical outcome in patients with crescentic nephritis.

Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy

To evaluate the effects of combined treatment of an ACE inhibitor and an angiotensin II receptor antagonist on parameters related to the progression of renal disease in type 2 diabetic patients. 20 hypertensive type 2 diabetic patients with non-nephrotic proteinuria (0.5 - 3.0 g/day) and estimated creatinine clearance > or = 40 ml/min/1.73m2 were randomly assigned to be treated with perindopril 8 mg/day (Per), irbesartan 300 mg/day (Irb) or a combination of both with the same doses (Per + Irb). Each treatment phase lasting 16 weeks was preceded by a four-week washout period. Diuretics, clonidine and hydralazine were used as supplementary drugs for blood pressure control. Patients were evaluated at baseline and at the end of each treatment phase. 15 (3M/12F) patients completed all the phases. Use of Per, Irb and Per + Irb led to a reduction in 24-hour mean blood pressure of 6 mmHg, 4 mmHg and 4 mmHg, respectively. Changes in glomerular filtration rate were not significant at any phase. Renal plasma flow was significantly more elevated with Irb than Per. Treatment with both Irb and Per + Irb induced similar plasma renin elevation, but treatment with Per did not, suggesting escape. Plasma aldosterone was reduced only by treatment with Per + Irb (-36%, p < 0.02). Reduction in proteinuria during Per + Irb (-33%) was not significantly different from Per (-34%) or Irb (-22%). Urinary transforming growth factor beta1 (TGF-beta1) excretion was significantly reduced with both Irb (-24%, p < 0.05) and Per + Irb (-36%, p < 0.05) but not with Per (-11%, p = 0.60). Only combined therapy with irbesartan plus perindopril concurrently reduces plasma aldosterone, proteinuria and urinary TGF-beta1.

Methylprednisolone favourably alters plasma and urinary cytokine homeostasis and subclinical renal injury at cardiac surgery

Whilst elevated urinary transforming growth factor beta-1 (TGFβ) is associated with chronic renal dysfunction its role in acute peri-operative renal dysfunction is unknown. In contrast, peri-operative increases in urinary IL-1 receptor antagonist (IL-1ra) and TNF soluble receptor-2 (TNFsr-2) mirror pro-inflammatory activity in the nephron and correlate with renal complications. Steroids modulate some plasma cytokines (decreasing TNFα, IL-8, IL-6 and increasing IL-10), whereas ability to reduce plasma and urinary TNFsr-2 and IL-1ra and peri-operative renal injury is unknown. Patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were randomised to receive methylprednisolone ( n=18) or placebo ( n=17) before induction of anaesthesia. Plasma and urinary pro- and anti-inflammatory cytokine balance was determined along with subclinical proximal tubular injury and dysfunction, measured by urinary N-acetyl-β- d-glucosaminidase (NAG)/creatinine and α-1-microglobulin/creatinine ratios, respectively. In the control group compared with baseline, plasma IL-8, TNFα, IL-10, IL-1ra and TNFsr-2 were significantly elevated along with urinary IL-1ra, TNFsr-2 and TGFβ1. Urinary NAG/creatinine and α-1-microglobulin/creatinine ratios rose from completion of revascularisation until 6 h with recovery at 24 h with a further rise in NAG/creatinine ratio at 48 h. Compared to placebo, the methylprednisolone group showed significantly reduced plasma IL-8, TNFα, IL-1ra and TNFsr-2 whereas plasma IL-10 increased. Compared to placebo, the methylprednisolone group demonstrated significantly reduced urinary NAG/creatinine ratio, TNFsr-2 and TGFβ1 at 24 h whereas urinary α-1-microglobulin/creatinine ratios increased. Conclusions Methylprednisolone administration during cardiac surgery significantly reduces plasma and urinary TNFsr-2 and IL-1ra, urinary TGFβ1 and subclinical renal injury but not dysfunction.

Factors Associated With the Outcomes of Children With Unilateral Ureteropelvic Junction Obstruction

Children with congenital unilateral ureteropelvic junction obstruction were evaluated with 99mtechnetium-labeled diethylenetriaminepentaacetic acid furosemide renal scans (DTPA) to determine the correlation of tubular function tests, growth factors and renal function. A total of 38 children diagnosed with congenital unilateral ureteropelvic junction obstruction and recipients of dismembered pyeloplasty were prospectively studied. Before pyeloplasty split renal tubular function, creatinine clearance, urinary growth factors and a marker for apoptosis of each kidney were examined. Renal function of the obstructed kidney was evaluated by DTPA before and after pyeloplasty. Initially patients with DTPA greater than 40% were designated group 1 and those with DTPA 40% or less were assigned to group 2. After surgery followup patients with DTPA greater than 40% were designated the well preserved group and those with DTPA 40% or less were assigned to the poorly preserved group. Statistical analyses were performed to determine the best predictive variable for treatment. Mean initial DTPA split renal function values of groups 1 and 2 were 47.3% and 28.8%, respectively and subsequently, they were 48.4% and 35.3%. Initial DTPA on the obstructed side of less than 35% had a 100% sensitivity and 100% positive predictive rate for a poorly preserved renal outcome. Among the various tubular functions, only percent fractional excretion of sodium and percent fractional excretion of chloride correlated with post-pyeloplasty DTPA. Urinary epidermal growth factor/creatinine correlated with preservation of renal function on postoperative DTPA renal scans. Although urinary transforming growth factor/creatinine levels and apoptosis ratios were higher on the obstructed side, they were not significantly different between the groups. Proximal tubular dysfunction, such as increased percent fractional excretion of sodium and chloride, and initial DTPA 35% or less, suggest a high possibility of poorly preserved renal outcome. Urinary transforming growth factor-beta1 and apoptosis are not correlated with renal outcome. A high urinary level of epidermal growth factor might be a potential indicator of preservation of renal growth.

Urinary transforming growth factor‐β1 levels correlate with bladder outlet obstruction

Urinary transforming growth factor-beta1 (TGF-beta1) levels have been shown to correlate with elevated intrapelvic pressure associated with ureteropelvic junction obstruction. Other studies have evaluated urinary TGF-beta1 levels in prostate cancer. This study tests the hypothesis that urinary TGF-beta1 levels might correlate with objective measures of bladder outlet obstruction (BOO). Twenty-three men (age: 46-85 years) with lower urinary tract symptoms underwent urodynamic studies consisting of non-invasive uroflowmetry, cystometrogram and voiding pressure flow studies. Patients were classified as obstructed (n = 17) or not obstructed (n = 6) based on Abrams-Griffith nomograms. Urinary TGF-beta1 was extracted from an aliquot of urine obtained at the time of bladder catheterization for urodynamic studies. Urinary TGF-beta1 levels were then determined by enzyme-linked immunosorbent assay (ELISA). There was a strong correlation between urinary TGF-beta1 levels and the presence of obstruction by Abrams-Griffith nomogram criteria (P = 0.025). Urinary TGF-beta1 levels were significantly higher in men with obstruction (0.039 +/- 0.011 pg/mL) than in men without obstruction (0.029 +/- 0.009 pg/mL; P = 0.036). Urinary TGF-beta1 levels correlate with objective measures of BOO. Further study is needed to test the utility of urinary TGF-beta1 as a non-invasive diagnostic tool for BOO.

Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice.

Ex vivo and in vitro observations implicate superoxide as a mediator of cell injury in diabetes, but in vivo evidence is lacking. In the current studies, parameters of glomerular injury were examined in hemizygous nondiabetic transgenic mice (SOD) and streptozotocin-diabetic (D) transgenic mice (D-SOD), which overexpress human cytoplasmic Cu2+/Zn2+ superoxide dismutase (SOD-1), and in corresponding wild-type littermates (WT, D-WT) after 4 months of diabetes. In both SOD and D-SOD mice, renal cortical SOD-1 activity was twofold higher than values in the WT mice; blood glucose and glycosylated hemoglobin (GHb) levels did not differ in the two diabetic groups. Urinary albumin excretion, fractional albumin clearance, urinary transforming growth factor-beta (TGF-beta) excretion, glomerular volume, glomerular content of immunoreactive TGF-beta, and collagen alpha1 (IV) and renal cortical malondialdehyde (MDA) levels were significantly higher in D-WT mice compared with corresponding values in D-SOD mice. Glomerular volume, glomerular content of TGF-beta and collagen IV, renal cortical MDA, and urinary excretion of TGF-beta in D-SOD mice did not differ significantly from corresponding values in either the nondiabetic SOD or WT mice. In separate groups of mice studied after 8 months of diabetes, mesangial matrix area, calculated as a fraction of total glomerular tuft area, and plasma creatinine were significantly higher in D-WT but not in D-SOD mice, compared with corresponding values in the nondiabetic mice. In vitro infection of mesangial cells (MC) with a recombinant adenovirus encoding human SOD-1 increased SOD-1 activity threefold over control cells and prevented the reduction of aconitase activity, an index of cellular superoxide, and the increase in collagen synthesis that otherwise occurred in control MC in response to culture with 300 or 500 mg/dl glucose. Thus, increases in cellular SOD-1 activity attenuate diabetic renal injury in vivo and also prevent stimulation of MC matrix protein synthesis induced in vitro by high glucose.

Urinary transforming growth factor-beta1 and alpha1-microglobulin in children and adolescents with type 1 diabetes.

Transforming growth factor (TGF)-beta1 is an important mediator in the pathogenesis of diabetic nephropathy. Urinary TGF-beta1 reflects TGF-beta1 production in the kidney, and alpha1-microglobulin tubular dysfunction. These 2 markers were studied in the early phases of type 1 diabetes. There were 113 type 1 diabetic children and adolescents (mean +/- SD: age 14.1 +/- 2.9 years, and diabetes duration 7.4 +/- 2.9 years, HbA1c 9.3 +/- 1.5%) and 39 healthy subjects (age 13.8 +/- 2.8 years) who participated in the study. Of the diabetic patients, 105 were normoalbuminuric (2-3 consecutive overnight urinary albumin excretion rates [AERs] <20 microg/min) and 8 had microalbuminuria (at least 2 AERs 20-200 microg/min). Overnight urinary TGF-beta1 and alpha1-microglobulin levels were measured and the results expressed as the ratio to urinary creatinine concentration. Data are medians (range). Diabetic patients had higher urinary TGF-beta1 levels than those of control subjects: 0.9 ng/mg (0.05-122.3) vs. 0.3 ng/mg (0.05-2.2) creatinine, respectively (P = 0.003). Urinary TGF-beta1 levels correlated with urinary glucose (r = 0.2, P = 0.03) and alpha1-microglobulin (r = 0.2, P = 0.02) levels, but not with HbA1c, AER, age, or duration of diabetes. In 43 patients with urinary TGF-beta1 above the control levels, urinary TGF-beta1 levels correlated with urinary glucose (r = 0.6, P < 0.001) and alpha1-microglobulin (r = 0.6, P < 0.001) levels. Diabetic patients had higher urinary alpha1-microglobulin levels than those of control subjects: 4.8 microg/mg (0.6-48.8) vs. 2.7 microg/mg (0.8-11.6) creatinine, respectively (P < 0.001). Alpha1-microglobulin levels correlated with AER (r = 0.2, P = 0.02), HbA1c (r = 0.3, P = 0.001), urinary glucose (r = 0.5, P < 0.001), and urinary TGF-beta1 levels. An early rise in urinary TGF-beta1 levels was observed in young type 1 diabetic patients. Urinary TGF-beta1 is associated with 2 interrelated tubular markers, alpha1-microglobulin and urinary glucose.