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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic retinopathy is a common complication of diabetes. It represents one of the frequent causes of visual disability among diabetic subjects during the period of active life. The risk factors for diabetic retinopathy are poor glycemic control, hypertension, duration of diabetes, hyperlipidemia and proteinuria. It has been observed that prevalence of hypertension is higher in diabetic subjects than in the general population and as it also plays a major role in the progression of diabetic retinopathy, so tight control of hypertension is mandatory. The possible mechanisms by which hypertension affects diabetic retinopathy are haemodynamic (impaired autoregulation and hyperperfusion) and secondly through VEGF (Vascular Endothelial Growth Factor), as it has been observed that hypertension independent of hyperglycaemia upregulates the VEGF expression in retinal endothelial cells and ocular fluids. The level of control of blood pressure are debatable but nearer the blood pressure to the normal levels, better the chances of preventing the onset and progression of diabetic retinopathy. The lowering of blood pressure to a normal range is more important than the type of antihypertensive medication used. Diabetic retinopathy is one of the important causes of visual disability in diabetic subjects during the period of active life. It is characterized by gradually progressive alterations in the retinal microvasculature, leading to increased vasopermeability, areas of retinal occlusion and retinal neovascularization. The complications associated with increased vasopermeability and uncontrolled neovascularization can result in severe and permanent visual loss.
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PMID:Does hypertension play a role in diabetic retinopathy? 1633 27

Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A). Non-Hodgkin's lymphoma patients with high serum VEGF levels have an inferior survival compared to patients with low VEGF levels. Bevacizumab was administered through a central line at 15 mg kg(-1) IV on day 1 followed by rituximab (R) and CHOP on day 2 for cycle 1 and day 1 for cycles 2 - 8. Serum levels of bevacizumab and R were measured at specified time points to assess pharmacokinetics (PK). Plasma and urine samples were also analysed for VEGF. Tumor samples were stained for VEGF, CD31 and factor VIII by immunohistochemistry. Thirteen patients with newly-diagnosed DLBCL received a total of 88 cycles (range 2 - 8, median 7). Best response included five CR, six PR, one SD and one PD with an overall response rate of 85% and complete response rate of 38%. The 12-month PFS is 77% and a median follow-up of 16.9 months for the surviving patients. All tumor samples stained strongly positive for VEGF and there was a marginal association between baseline plasma VEGF and response (p = 0.04). Patients with higher plasma VEGF levels were generally younger and had bulky disease. Micro-vessel density did not correlate with presenting disease characteristics, VEGF expression or response. The PK of bevacizumab and rituximab were not influenced by combined treatment. In this patient population, treatment with RA-CHOP did not result in any episodes of grade 3 or 4 proteinuria, heart failure or hemorrhage. The RA-CHOP combination was generally well tolerated and safe.
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PMID:Rituximab, bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis. 1684 Jan 82

Bevacizumab represents the first humanized monoclonal antibody with antiangiogenic properties which has been introduced in clinical oncology. The VEGF antagonist is used for the treatment of advanced colorectal cancer based on significant survivial benefits. Besides hypertension, proteinuria, wound healing disorders, bleeding and thromboembolic events appear to be related to bevacizumab. Optimization of combination therapy, new potential indications as well as pharmacoeconomic considerations represent the topics of current discussion regarding the novel monoclonal antibody.
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PMID:[Bevacizumab. Progress in cancer therapy by antiangiogenesis]. 1686 78

Angiogenesis is the process by which new blood vessels are created from pre-existing vessels. It is essential for the growth and development of normal cells and tissues during embryonic and neonatal development and of tumour cells. Solid tumours rely on having an extensive network of blood vessels for growth and survival. The key mediator of angiogenesis, vascular endothelial growth factor-A (VEGF-A), is critical for the growth of tumours and their subsequent metastasis and is known to initiate angiogenesis. Bevacizumab is a humanized immunoglobulin G monoclonal antibody that binds to VEGF with high specificity, thereby blocking VEGF-mediated signalling pathways and thus angiogenesis. Clinical trials have shown that bevacizumab is effective in prolonging survival in patients with metastatic colorectal cancer (CRC) when combined with standard chemotherapy. Consequently, bevacizumab has been approved in combination with 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic CRC. Bevacizumab is generally well tolerated in most patients and does not exacerbate the adverse events associated with conventional chemotherapy. Bevacizumab-related side effects are generally manageable; however, monitoring for hypertension, gastrointestinal perforation, bleeding, proteinuria and thromboembolism is advised, especially in patients with predisposing factors. In addition to demonstrated survival benefits, the convenient dosing schedule and lack of interactions should ensure the successful integration of this novel agent into clinical practice.
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PMID:Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer. 1728 84

Diabetic nephropathy (DN), the most common cause of end stage renal disease in developed nations, is thought to result from interactions between metabolic and haemodynamic factors. Specific metabolically driven, glucose dependent pathways are activated within diabetic renal tissues. These pathways induce oxidative stress, polyol pathway flux, hexosamine flux and accumulation of advanced glycated end-products (AGEs). Haemodynamic factors are also implicated in the pathogenesis of DN and include elevations of systemic and intraglomerular pressure and activation of various vasoactive hormone pathways including the renin-angiotensin aldosterone system (RAAS), endothelin and urotensin. These altered hemodynamics act independently and in concert with metabolic pathways, to activate intracellular second messengers such as protein kinase C (PKC) and MAP kinase (MAPK), nuclear transcription factors such as nuclear factor-kappaB (NF-kappaB) and various growth factors such as the prosclerotic cytokines, transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the angiogenic, permeability enhancing growth factor, vascular endothelial growth factor, VEGF. Ultimately these molecular mechanisms lead to increased renal albumin permeability, and extracellular matrix accumulation, which results in increasing proteinuria, glomerulosclerosis and tubulointerstitial fibrosis. In the past, the treatment of diabetic nephropathy has focused on control of hyperglycemia and the interruption of the RAAS with certain anti-hypertensive agents. Newer novel targets, some of which are linked to glucose dependent pathways, appear to be a major focus of new therapies directed against the development and progression of renal damage as a result of diabetes. It is likely that resolution of diabetic nephropathy will require synergistic therapies to target multiple mediators of this disease.
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PMID:Diabetic nephropathy: where hemodynamics meets metabolism. 1731 65

One of the earliest clinically detectable abnormalities in diabetic nephropathy is microalbuminuria that eventually progresses to proteinuria. The degree of proteinuria correlates with the progression of glomerulosclerosis and tubulointerstitial fibrosis. In the glomerulus, a typical podocytopathy develops that participates in the initiation of glomerulosclerosis and the accelerated plasma protein leakage across the glomerular basement membrane (GBM) into Bowman's space. Downstream into the tubular compartment, the proteinuria induces proinflammatory and profibrogenetic injury in tubular cells which can facilitate the development of interstitial fibrosis and tubular atrophy. It has long been held that hemodynamic changes and the loss of negatively charged proteoglycans in the GBM are important mediators of proteinuria. More recently, biopsy studies in humans with diabetic kidney disease have provided strong evidence that podocytes are injured very early in the course of nephropathy. This podocytopathy--which is characterized by decreased podocyte number and/or density, GBM thickening and altered matrix composition, and foot process effacement--correlates closely with the development and progression of albuminuria. Components of the diabetic milieu (high glucose, accumulation of glycated proteins, high intrarenal angiotensin II (ANG II), and hypertension-induced mechanical stress) result in activation of cytokine systems, the most important of which are transforming growth factor-beta1 (TGF-beta1) and vascular endothelial growth factor-A (VEGF-A). ANG II-stimulated podocyte-derived VEGF, through a novel autocrine signaling loop, appears to be a major cause of nephrin downregulation and the development of proteinuria. Nephrin is an important protein of the slit diaphragm with anti-apoptotic signaling properties. TGF-beta1 causes podocyte apoptosis and an increase in extracellular matrix deposition. As a consequence, the denuded GBM adheres to Bowman's capsule initiating the development of glomerulosclerosis. Good control of hyperglycemia and hypertension and maximal inhibition of ANG II are essential steps in preventing the development and progression of diabetic nephropathy.
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PMID:Cellular and molecular mechanisms of proteinuria in diabetic nephropathy. 1757 Sep 45

Over the last five years, much work has underlined the important role of the podocyte in the development of diabetic nephropathy. The metabolic and haemodynamic abnormalities of the diabetic milieu act in concert, perhaps via the common effector path of oxidative stress and development of reactive oxygen species, to promote podocyte damage. There is loss of nephrin from the slit diaphragm, increased synthesis of some of the components of the glomerular basement membrane, activation of pro-apoptotic and hypertrophic pathways, loss of the alpha3beta1 integrin and increased secretion of VEGF. These changes interact to lead to increased permeability, accumulation of abnormal extracellular matrix, apoptosis, foot process detachment and podocyte loss. The foot processes of the remaining podocytes hypertrophy and widen, with reduced filtration slit width. The end result is increasing proteinuria, basement membrane thickening and accumulation of mesangial matrix and declining renal function. Some currently used therapies, such as tight glucose control and inhibition of the renin angiotensin system, ameliorate these changes and prevent podocyte loss. Statins may also have a specific podocyte protective role. Other potential therapies include inhibitors of glycation, antioxidants, and inhibitors of growth factor and signalling pathways.
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PMID:The podocyte: a potential therapeutic target in diabetic nephropathy? 1789 15

In this study, serum and urinary VEGF levels and VEGF expression in PBMNC were correlated with daily proteinuria, renal function tests, and renal histopathologic findings in untreated patients with different glomerulonephritis and with the course of renal function and proteinuria for one year. Forty-five untreated patients with different glomerulonephritis and 11 healthy persons comprised the study and control groups, respectively. VEGF mRNA expression was detected by RT- PCR in peripheral blood mononuclear cells (PBMNC), and VEGF levels were measured by ELISA in serum and urine samples simultaneously. Male/female ratio was 24/21 and mean ages were 34.49 +/- 14.98. Serum and urinary VEGF levels, VEGF expressions in PBMNC, and the ratios of urine VEGF/urine creatinine were found to be similar in patients and controls. There were important correlations between urinary VEGF levels and baseline serum Cr (p = 0.035) and ESR (p = 0.022). There was also a marginal correlation between urinary VEGF levels and baseline CCr (p = 0.072). There was no correlation between serum and urinary VEGF levels and PBMNC mRNA expression and pathological findings such as with or without glomerular sclerosis, tubulointerstitial fibrosis (TIF), periglomerular fibrosis, and mesangial cell proliferation in renal biopsy. Serum and urinary VEGF levels or VEGF expression in PBMNC in patients with renal amyloidosis or proliferative or nonproliferative glomerulonephritis were similar with that of healthy controls and each other. Serum and urinary VEGF levels and PBMNC VEGF mRNA expression in untreated patients with different glomerulonephritis and controls were similar. We found only one important correlation, that between urinary VEGF levels and baseline serum creatinine levels in patients with different glomerulonephritis. Urinary VEGF can be an important pathogenesis of glomerular disease or a simple proteinuria. Serum and urinary VEGF levels and PBMNC VEGFmRNA did not change by periglomerular sclerosis, periglomerular fibrosis, or tubulointerstitial fibrosis on renal biopsy. PBMNC VEGF mRNA expression decreased in patients undergoing remission. In addition to the important correlation between urinary VEGF and serum creatinine, we also found an important correlation between erythrocyte sedimentation rate and urinary VEGF. This finding was interesting because we could not find a similar conclusion in other studies.
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PMID:The relationship between the VEGF levels and VEGF mRNA expression and clinical course in different glomerulonephritis. 1799 43

The angiogenesis inhibitor bevacizumab, a VEGF antagonist, was approved in the European Union in August 2007 for the first-line therapy of inoperable, advanced or recurrent non-small-cell lung cancer, in combination with a platin-based chemotherapy regimen. Tumors with predominantly squamous-cell histology must be excluded. Two recent phase-III studies have shown that bevacizumab, combined with carboplatin and paclitaxel (E4599) or cisplatin and gemcitabine (AVAiL), significantly prolongs overall survival and/or progression-free survival. The most common adverse events during therapy with bevacizumab are hypertension and proteinuria - both are usually well manageable. By applying correct patient selection criteria the risk of pulmonary bleeding can be greatly reduced.
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PMID:[Bevacizumab in the first-line therapy of advanced NSCLC]. 1815 97

In preeclampsia (PE), proteinuria has been associated with a reduced expression of nephrin by podocytes. In the present study, we investigated in vitro on human cultured podocytes the mechanism responsible for nephrin loss in PE. Sera from patients with PE did not directly downregulate the expression of nephrin. In contrast, conditioned medium obtained from glomerular endothelial cells incubated with PE sera induced loss of nephrin and synaptopodin, but not of podocin, from podocytes. Nephrin loss was related to a rapid shedding of the protein from the cell surface due to cleavage of its extracellular domain by proteases and to cytoskeleton redistribution. The absence of nephrin mRNA downregulation together with nephrin reexpression within 24 h confirm that the loss of nephrin was not related to a reduced synthesis. Studies with an endothelin-1 (ET-1) receptor antagonist that abrogated the loss of nephrin triggered by glomerular endothelial conditioned medium of PE sera indicated that ET-1 was the main effector of nephrin loss. Indeed, ET-1 was synthesized and released from glomerular endothelial cells when incubated with PE sera, and recombinant ET-1 triggered nephrin shedding from podocytes. Moreover, VEGF blockade induced ET-1 release from endothelial cells, and in turn the conditioned medium obtained triggered nephrin loss. In conclusion, the present study identifies a potential mechanism of nephrin loss in PE that may link endothelial injury with enhanced glomerular permeability.
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PMID:Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. 1828 2


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