epidermal-growth-factor and Albuminuria

To compare the effect of the antihypertensive drugs nitrendipine and enalapril on the excretion of epidermal growth factor (EGF) and albumin in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) subjects.. After a 4-week washout period, mildly hypertensive (systolic blood pressure [sBP] > or = 140 mmHg and/or diastolic blood pressure [dBP] > or = 90 mmHg) NIDDM patients with albuminuria (15-200 micrograms/min) were randomized into an 8-month-long therapy with either nitrendipine (n = 11) or enalapril (n = 10). Blood pressure, EGF, and microalbumin excretion were measured at baseline and throughout the treatment period.. A significant fall in sBP was noticed in the enalapril group and in dBP in the nitrendipine group. In the enalapril group, EGF excretion progressively increased from 188 to 214 nmol/mmol creatinine after 6 weeks and to 274 after 8 months of therapy (P = 0.03). There was a significant fall in albumin excretion while patients were on enalapril, but in the nitrendipine group, neither albuminuria nor EGF excretion changed significantly. There was no correlation of improved EGF excretion with a decrease in albuminuria or BP.. The angiotensin-converting enzyme inhibitor enalapril has been effective in decreasing albumin and increasing EGF excretion. Measurement of urinary EGF may provide a new valuable index of renal function.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enalapril; Epidermal Growth Factor; Humans; Hypertension; Middle Aged; Nitrendipine

Topics: Albuminuria; Angiopoietin-1; Angiopoietin-2; Animals; Diabetes Mellitus; Diabetic Nephropathies; Epidermal Growth Factor; Mice; Mice, Obese; Protein-Tyrosine Kinases

Micro-albuminuria is considered an early clinical sign of diabetes nephropathy, however, early decrease of glomerular filtration can be present years before the presence of microalbuminuria. In this study, we explored whether urinary epidermal growth factor (uEGF) might serve as an early marker of diabetes nephropathy compared to microalbuminuria in children and adolescents.. Children with type 1 diabetes mellitus (n = 158) and healthy controls (n = 40) were included in this study. Serum and urine samples were collected three times with an interval of at least one month to determine creatinine (serum and urine), epidermal growth factor and albumin (urine). Demographic data and routine lab values were extracted out of the electronic patient files.. uEGF was significantly lower in children with T1DM compared to healthy controls (p = 0.032). A relatively lower glomerular filtration rate (eGFR) was associated with a decreased uEGF (p < 0.001). uEGF was independently associated with eGFR in a multivariate analysis.. This study provides evidence that uEGF can serve as an early marker of diabetes nephropathy in children and adolescents.

Topics: Adolescent; Albuminuria; Biomarkers; Child; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Glomerular Filtration Rate; Humans; Kidney

The development of metabolic syndrome-associated renal dysfunction is exacerbated by a number of factors including dyslipidemia, ectopic deposition of lipids and their toxic metabolites, impairment of lipid metabolism, and insulin resistance. Renal dysfunction is also affected by the production of proinflammatory and profibrotic factors secreted from adipose tissue, which can in turn directly impair kidney cells and potentiate insulin resistance. In this study, we investigated the manifestation of renal lipid accumulation and its effect on renal dysfunction in a model of metabolic syndrome-the hereditary hypertriglyceridemic rat (HHTg)-by assessing microalbuminuria and targeted urinary proteomics. Male Wistar control rats and HHTg rats were fed a standard diet and observed over the course of ageing at 3, 12, and 20 months of age.. Chronically elevated levels of triglycerides in HHTg rats were associated with increased levels of NEFA during OGTT and over a period of 24 hours (+80%,. Our results confirm dyslipidemia and ectopic lipid accumulation to be key contributors in the development of metabolic syndrome-associated renal dysfunction. Assessing urinary secretion of proinflammatory cytokines and epidermal growth factor can help in detecting early development of metabolic syndrome-associated renal dysfunction.

Topics: Albuminuria; Animals; Biomarkers; Cytokines; Disease Models, Animal; Early Diagnosis; Epidermal Growth Factor; Hypertriglyceridemia; Inflammation Mediators; Kidney Diseases; Lipids; Male; Metabolic Syndrome; Predictive Value of Tests; Proteomics; Rats, Transgenic; Rats, Wistar; Time Factors; Urinalysis

To identify determinants of early progressive renal decline in type 2 diabetes a range of markers was studied in 1032 patients enrolled into the 2nd Joslin Kidney Study. eGFR slopes estimated from serial measurements of serum creatinine during 5-12 years of follow-up were used to define early renal decline. At enrollment, all patients had normal eGFR, 58% had normoalbuminuria and 42% had albuminuria. Early renal decline developed in 6% and in 18% patients, respectively. As determinants, we examined baseline values of clinical characteristics, circulating markers: TNFR1, KIM-1, and FGF23, and urinary markers: albumin, KIM-1, NGAL, MCP-1, EGF (all normalized to urinary creatinine) and the ratio of EGF to MCP-1. In univariate analysis, all plasma and urinary markers were significantly associated with risk of early renal decline. When analyzed together, systolic blood pressure, TNFR1, KIM-1, the albumin to creatinine ratio, and the EGF/MCP-1 ratio remained significant with the latter having the strongest effect. Integration of these markers into a multi-marker prognostic test resulted in a significant improvement of discriminatory performance of risk prediction of early renal decline, compared with the albumin to creatinine ratio and systolic blood pressure alone. However, the positive predictive value was only 50% in albuminuric patients. Thus, markers in plasma and urine indicate that the early progressive renal decline in Type 2 diabetes has multiple determinants with strong evidence for involvement of tubular damage. However, new, more informative markers are needed to develop a better prognostic test for such decline that can be used in a clinical setting.

Topics: Adult; Albuminuria; Biomarkers; Blood Pressure; Chemokine CCL2; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Early Diagnosis; Epidermal Growth Factor; Female; Fibroblast Growth Factor-23; Glomerular Filtration Rate; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney; Male; Middle Aged; Predictive Value of Tests; Prognosis; Receptors, Tumor Necrosis Factor, Type I; Risk Assessment; Risk Factors; Time Factors

Increased monocyte chemoattractant protein-1 (MCP-1) and decreased epidermal growth factor (EGF) are promising biomarkers to predict progressive decline in kidney function in non-diabetic kidney diseases. We aimed to evaluate the performance of urinary EGF, MCP-1 or their ratio in predicting rapid decline of GFR in a cohort of Type 2 diabetic patients (T2DM) with diabetic kidney disease (DKD).. T2DM patients (n = 83) with DKD at high risk for renal progression were followed up prospectively. The baseline urine values of MCP-1 to creatinine ratio (UMCP-1), EGF to creatinine ratio (UEGF), EGF to MCP-1 ratio (UEGF/MCP-1) and albumin to creatinine ratio (UACR) were measured. The primary outcome was a decline in estimated glomerular filtration rate (GFR) of ≥25% yearly from baseline.. During follow-up time of 23 months, patients with rapid decline in estimated GFR of ≥25% yearly from baseline had significantly higher baseline levels of UMCP-1, and UACR and lower UEGF and UEGF/MCP-1 ratio. All renal biomarkers predicted primary outcomes with ROC (95%CI) for UMCP-1=0.73 (0.62-0.84), UEGF=0.68 (0.57-0.80), UEGF/MCP-1=0.74 (0.63-0.85), and UACR =0.84 (0.75-0.93). By univariate analysis, blood pressure, GFR, UACR, UMCP-1, UEGF, and UEGF/MCP-1 were associated with rapid decline GFR. By multivariate analysis, UACR, systolic blood pressure, and UMCP-1 or UEGF/MCP-1 were independently associated with rapid GFR decline.. UMCP-1 or UEGF/MCP-1 ratio were associated with rapid renal progression independent from conventional risk factors in DKD.

Topics: Aged; Albuminuria; Biomarkers; Cardiovascular Diseases; Chemokine CCL2; Creatinine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Prospective Studies; Risk Factors

Kidney injury with proteinuria is a characteristic feature of preeclampsia, yet the nature of injury in specific regions of the nephron is incompletely understood. Our study aimed to use existing urinary biomarkers to describe the pattern of kidney injury and proteinuria in pregnancies affected by severe preeclampsia. We performed a case-control study of pregnant women from Brigham and Women's Hospital from 2012 to 2013. We matched cases of severe preeclampsia (n=25) 1:1 by parity and gestational age to 2 control groups with and without chronic hypertension. Urinary levels of kidney injury molecule-1 and complement components (C3a, C5a, and C5b-9) were measured by enzyme-linked immunosorbent assay, and other markers (albumin, β2 microglobulin, cystatin C, epithelial growth factor, neutrophil gelatinase-associated lipocalin, osteopontin, and uromodulin) were measured simultaneously with a multiplex electrochemiluminescence assay. Median values between groups were compared with the Wilcoxon signed-rank test and correlations with Spearman correlation coefficient. Analysis of urinary markers revealed higher excretion of albumin and kidney injury molecule-1 and lower excretion of neutrophil gelatinase-associated lipocalin and epithelial growth factor in severe preeclampsia compared with chronic hypertension and healthy controls. Among subjects with severe preeclampsia, urinary excretion of complement activation products correlated most closely with kidney injury molecule-1, a specific marker of proximal tubule injury (C5a: r=0.60; P=0.001; and C5b-9: r=0.75; P<0.0001). Taken together, we describe a pattern of kidney injury in severe preeclampsia that is characterized by glomerular impairment and complement-mediated inflammation and injury, possibly localized to the proximal tubule in association with kidney injury molecule-1.

Topics: Acute-Phase Proteins; Adult; Albuminuria; beta 2-Microglobulin; Biomarkers; Case-Control Studies; Complement Activation; Complement C3a; Complement C5a; Complement Membrane Attack Complex; Epidermal Growth Factor; Female; Hepatitis A Virus Cellular Receptor 1; Humans; Kidney Tubules, Proximal; Lipocalin-2; Lipocalins; Membrane Glycoproteins; Osteopontin; Pre-Eclampsia; Pregnancy; Proto-Oncogene Proteins; Receptors, Virus; Severity of Illness Index; Uromodulin

Activation of signal transducer and activator of transcription (STAT)3 correlates with proliferation of extracapillary glomerular epithelial cells and the extent of renal injury in glomerulonephritis. To delineate the role of STAT3 in glomerular epithelial cell proliferation, we examined the development of nephrotoxic serum-induced glomerulonephritis in mice with and without podocyte-restricted STAT3 deletion. Mice with STAT3 deletion in podocytes developed less crescents and loss of renal function compared with those without STAT3 deletion. Proliferation of glomerular cells, loss of podocyte markers, and recruitment of parietal epithelial cells were found in nephritic mice without STAT3 deletion, but mitigated in nephritic mice with podocyte STAT3 deletion. Glomerular expression of pro-inflammatory STAT3 target genes was significantly reduced in nephritic mice with, compared with those without, podocyte STAT3 deletion. However, the extent of glomerular immune complex deposition was not different. Podocytes with STAT3 deletion were resistant to interleukin-6-induced STAT3 phosphorylation and pro-inflammatory STAT3 target gene expression. Thus, podocyte STAT3 activation is critical for the development of crescentic glomerulonephritis.

Topics: Albuminuria; Animals; Antigen-Antibody Complex; Apoptosis; Cell Line; Cell Proliferation; Complement C3; Disease Models, Animal; Epidermal Growth Factor; Glomerulonephritis; Immunoglobulins; Inflammation Mediators; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Podocytes; Primary Cell Culture; Serum; Signal Transduction; STAT3 Transcription Factor; Time Factors

The aim of this study was to examine the effect of protein kinase Cbeta inhibition with ruboxistaurin on renal hemodynamic function and urinary biomarkers (monocyte chemoattractant protein-1 [MCP-1] and epidermal growth factor) in renin angiotensin system blockade-treated type 1 diabetic subjects.. Albuminuric subjects were randomized (2:1) to ruboxistaurin (32 mg daily; n = 13) or placebo (n = 7) for 8 weeks. Renal hemodynamic function was measured during clamped euglycemia or hyperglycemia and before and after ruboxistaurin or placebo.. Ruboxistaurin was not associated with between-group differences during clamped euglycemia or hyperglycemia. In a post hoc analysis comparing hyperfilterers with normofilterers during euglycemia, glomerular filtration rate and MCP-1 decreased, whereas the epidermal growth factor-to-MCP-1 ratio increased in hyperfilterers versus normofilterers (all P < 0.05).. The effect of ruboxistaurin is modest and dependent, at least in part, on the level of ambient glycemia and baseline glomerular filtration rate.

Topics: Albuminuria; Blood Pressure; Chemokine CCL2; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Enzyme Inhibitors; Epidermal Growth Factor; Glomerular Filtration Rate; Hemodynamics; Humans; Indoles; Kidney; Maleimides; Protein Kinase C; Protein Kinase C beta

Our previous work in the acute puromycin aminonucleoside nephrosis (PAN) model has demonstrated up-regulation of heparin-binding epidermal growth factor-like growth factor (HB-EGF) mRNA and protein within glomerular epithelial cells (GECs) prior to the onset of proteinuria.. To determine whether increased HB-EGF expression in the acute PAN model contributes to the pathogenesis of proteinuria, a monoclonal antibody (DE10) was produced against recombinant human HB-EGF.. The specificity of DE10 for human HB-EGF was confirmed by enzyme-linked immunosorbent assay, immunohistochemical staining, and flow cytometry of transfected cells expressing human and rat HB-EGF, and inhibition of cell proliferation. DE10 also reacted with cells transfected with rat HB-EGF cDNA. Administration of 0.5 mg affinity-purified DE10 to normal rats did not cause significant albuminuria compared with controls. Five days after the induction of the acute PAN model, albuminuria was significantly greater in animals treated with 0.5 mg DE10 than a control mAb (162.6 +/- 32.4 vs. 64.8 +/- 10.2 mg/day, respectively, P < 0.01). Rats treated with DE10 had an earlier onset of severe albuminuria, but no increase in maximal albuminuria at later time points. Electron microscopy showed marked podocyte effacement in both DE10-treated and control animals, but no obvious difference between groups. However, adhesion of the human GEC line 56/10 A1 to laminin and fibronectin, but not to collagens I or IV, was reduced by DE10.. This study suggests that HB-EGF contributes to the integrity of the glomerular filtration barrier, particularly when the podocyte has been injured. Following podocyte injury, adhesion to laminin in the glomerular basement membrane by HB-EGF may be important in reducing albuminuria.

Topics: 3T3 Cells; Actins; Albuminuria; Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antibody Specificity; Cell Adhesion; CHO Cells; COS Cells; Cricetinae; Epidermal Growth Factor; Female; Flow Cytometry; Glomerular Filtration Rate; Heparin-binding EGF-like Growth Factor; Humans; Integrin alpha3beta1; Integrins; Intercellular Signaling Peptides and Proteins; Kidney; Mice; Mice, Inbred BALB C; Microscopy, Confocal; Microscopy, Electron; Nephrosis; Neutralization Tests; Puromycin Aminonucleoside; Rats; Transfection

Urinary epidermal growth factor (EGF) excretion is seen as a marker of tubular function, and some studies conclude that EGF excretion can already be reduced early in the development of diabetic renal disease. It is even suggested that EGF could play a role in kidney and glomerular enlargement and hypertrophy in diabetic subjects. We have investigated various groups of subjects, namely healthy controls (n = 5), patients with non-diabetic chronic renal insufficiency (n = 10), and normoalbuminuric (n = 9), microalbuminuric (n = 13) and nephropathic (n = 9) insulin-dependent diabetic subjects. In all subjects glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using a continuous infusion of 125I-iothalamate and 131I-hippuran, respectively. Diabetic subjects were tested during (near) normoglycaemic conditions. During the renal function test urine was collected for EGF measurement (in ng). With lower GFR values, EGF excretion/min was also lower. GFR correlated well with EGF/min (r = 0.63, p < 0.001). Fractional EGF clearance (EGF/GFR) was comparable in all groups. There was no correlation between urinary albumin excretion rate and EGF excretion in the diabetic subjects (r = -0.18, n.s.) and in all subjects (r = -0.12, n.s.). There was a significant correlation between UAER and GFR (r = -0.51, p < 0.005). No significant correlation could be found between urinary albumin excretion rate (UAER) and EGF/GFR (r = -0.07, n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Albuminuria; Biomarkers; Blood Flow Velocity; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Circulation

Morning urine samples were assayed for human EGF (hEGF) in 137 non-insulin dependent diabetic patients with normal serum creatinine and beta 2-microglobulin levels. Serving as controls, 80 age- and sex-matched healthy subjects were also examined. A significant positive correlation between hEGF excretion and the level of hemoglobin A1C (HbA1c) was present in those patients with a HbA1c value exceeding 8% (r = 0.37; p = 0.003) but not in the overall patients. The urinary hEGF level did not correlate with the concentration of glucose in urine or plasma. The mean urinary hEGF level of diabetic patients was significantly lower than that of healthy subjects. The mean urinary hEGF level was significantly lower in the patients with a diabetic history that exceeded five years as compared with those with a history below five years. The mean urinary hEGF level was significantly lower in the patients with retinopathy vs. those without retinopathy. In the patients with HbA1c value below 8%, the mean urinary hEGF level was lower in the patients whose urinary albumin level exceeded 1.7 mg/mmol.creatinine as compared with those whose urinary albumin excretion was below 1.7 mg/mmol.creatinine. These findings suggest that urinary hEGF excretion may decrease with the progression of diabetic complications in the patients with well-controlled glycemia, and that inadequate glycemic control may lead to an increased excretion of urinary hEGF in the early disease stage.

Topics: Adult; Aged; Albuminuria; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Epidermal Growth Factor; Female; Glycosuria; Humans; Male; Middle Aged; Radioimmunoassay

To study the relationship between glomerular and tubular function we investigated glomerular filtration rate (GFR), urinary albumin excretion, and urinary excretion of epidermal growth factor (EGF, a mitogenic peptide synthesized in the renal tubular cells) in normal subjects (group I, n = 7) and in Type 1 (insulin-dependent) diabetic patients with normoalbuminuria (group II, n = 11); with incipient nephropathy (microalbuminuria) (group III, n = 9); with nephropathy and normal GFR (group IV, n = 12); and with reduced GFR (group V, n = 8). EGF (nmol 24 h-1) decreased with progressive glomerular involvement, from 7.9 (4.1-10.5) (median and range) in group I, to 6.7 (1.3-9.2) in group II, 5.0 (3.6-7.4) in group III, 4.1 (2.5-9.5) in group IV, and 1.1 (0.1-2.5) in group V. The urinary excretion of EGF was significantly reduced in patients with elevated UAE (group III, IV, and V) compared with normal control subjects (p less than 0.05). A significant correlation between urinary excretion of EGF and GFR (r = 0.71, p less than 0.001) and an inverse correlation between the urinary excretion of EGF and albumin (r = -0.35, p less than 0.05) was demonstrated in the Type 1 diabetic patients with GFR greater than 90 ml min-1. Our study demonstrates that urinary excretion of epidermal growth factor diminishes with increasing nephron impairment, and that renal tubular function as judged by the excretion of EGF is reduced early in the development of diabetic kidney disease.

Topics: Adult; Albuminuria; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Epidermal Growth Factor; Female; Glomerular Filtration Rate; Humans; Male; Reference Values

Epidermal growth factor (EGF) is a polypeptide mitogen first isolated from mouse submaxillary glands and later from human urine. We have examined the pattern of urinary excretion of human EGF (hEGF) in normal subjects and in diabetic patients with varying degrees of nephropathy. hEGF was measured by homologous radioimmunoassay and expressed in terms of urinary creatinine excretion. On the basis of their albumin excretion rate, the diabetic patients were divided into those with normoalbuminuria (albumin excretion rate 3.5 (1.4-9.8) micrograms/min; mean (range)), microalbuminuria (albumin excretion rate 75 (30-128) micrograms/min) and macroalbuminuria (289 (169-879) micrograms/min). The albumin excretion rate for the normal subjects was 3.7 (1.6-9.7) micrograms/min. The mean (range) hEGF excretion (nmol hEGF/mmol creatinine) was 0.69 (0.47-1.29) for 19 healthy subjects, 0.60 (0.16-1.36) for the normoalbuminuric group (n = 18; NS), 0.47 (0.10-0.83) for the microalbuminuric patients (n = 19; P less than 0.001 vs controls and normoalbuminuric diabetics) and 0.38 (0.10-0.63) for the macroalbuminuric group (n = 18; P less than 0.001 vs controls and normoalbuminuric diabetics). There was an inverse correlation between albumin excretion rate and hEGF: creatinine ratio (r = -0.49; P = 0.02). These results show a progressive decline in hEGF excretion in diabetic patients with varying degrees of nephropathy and do not support the hypothesis that increased kidney size seen in early nephropathy is due to excessive amounts of EGF in the urine.

Topics: Adult; Albuminuria; Diabetic Nephropathies; Epidermal Growth Factor; Female; Humans; Male; Middle Aged