Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive renal failure continues to be a challenge. The use of bone marrow cells represents a means of meeting that challenge. We used lineage-negative (Lin(-)) cells to test the hypothesis that Lin(-) cell treatment decreases renal injury. Syngeneic Fischer 344 rats were divided into four groups: sham (laparotomy only, untreated); Nx (five-sixth nephrectomy and untreated); NxLC1 (five-sixth nephrectomy and receiving 2 x 10(6) Lin(-) cells on postnephrectomy day 15); and NxLC3 (five-sixth nephrectomy and receiving 2 x 10(6) Lin(-) cells on postnephrectomy days 15, 30, and 45). On postoperative day 16, renal mRNA expression of interleukin (IL)-1beta, tumor necrosis factor-alpha, and IL-6 was lower in NxLC rats than in Nx rats. On postnephrectomy day 60, NxLC rats presented less proteinuria, glomerulosclerosis, anemia, renal infiltration of immune cells, and protein expression of monocyte chemoattractant protein-1, as well as decreased interstitial area. Immunostaining for proliferating cell nuclear antigen showed that, in comparison with sham rats, Nx rats presented greater cell proliferation, whereas NxLC1 rats and NxLC3 rats presented less cell proliferation than did Nx rats. Protein expression of the cyclin-dependent kinase inhibitor p21 and of vascular endothelial growth factor increased after nephrectomy and decreased after Lin(-) cell treatment. On postnephrectomy day 120, renal function (inulin clearance) was significantly better in Lin(-) cell-treated rats than in untreated rats. Lin(-) cell treatment significantly improved survival. These data suggest that Lin(-) cell treatment protects against chronic renal failure.
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PMID:Lineage-negative bone marrow cells protect against chronic renal failure. 1909 42

Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.
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PMID:Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. 1912 59

Proteinuria, inflammation, chronic hypoxia, and rarefaction of peritubular capillaries contribute to the progression of renal disease by affecting proximal tubular epithelial cells (PTECs). To study the transcriptional response that separates patients with a stable course from those with a progressive course of disease, we isolated PTECs by laser capture microdissection from cryocut tissue sections of patients with proteinuric glomerulopathies (stable n=20, progressive n=11) with a median clinical follow-up of 26 months. Gene-expression profiling and a systems biology analysis identified activation of intracellular vascular endothelial growth factor (VEGF) signaling and hypoxia response pathways in progressive patients, which was associated with upregulation of hypoxia-inducible-factor (HIF)-1alpha and several HIF target genes, such as transferrin, transferrin-receptor, p21, and VEGF-receptor 1, but downregulation of VEGF-A. The inverse expression levels of HIF-1alpha and VEGF-A were significantly superior in predicting clinical outcome as compared with proteinuria, renal function, and degree of tubular atrophy and interstitial fibrosis at the time of biopsy. Interactome analysis showed the association of attenuated VEGF-A expression with the downregulation of genes that usually stimulate VEGF-A expression, such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and HIF-2alpha. In vitro experiments confirmed the positive regulatory effect of EGF and IGF-1 on VEGF-A transcription in human proximal tubular cells. Thus, in progressive but not in stable proteinuric kidney disease, human PTECs show an attenuated VEGF-A expression despite an activation of intracellular hypoxia response and VEGF signaling pathways, which might be due to a reduced expression of positive coregulators, such as EGF and IGF-1.
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PMID:Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease. 1913 26

There is scant knowledge on the changes in renal histological findings in type 1 diabetic patients those initially had nephrotic proteinuria and decreased renal function and later had complete remission of diabetic nephropathy by multifactorial treatment (MFT). A 44-year-old Japanese type 1 diabetic woman (duration of diabetes: 17 years) with massive proteinuria (2.9 g/day) and decreased renal function (creatinine clearance rate (Ccr): 86 mL/min) was admitted. Aggressive MFT was started with intensive insulin treatment, a low protein and low salt diet, angiotensin converting enzyme inhibitor and a diuretic. Her levels of HbA1c decreased to less than 7% within 4 months, and her high blood pressure gradually decreased and remained around mean 116/68 mmHg. Her Ccr level gradually improved and reached 108 mL/min after 78 months. Her first renal biopsy performed before MFT demonstrated diffuse and/or global accumulation of periodic acid-Schiff staining-positive mesangial matrix with increased mesangial matrix/glomerulus ratio and tubulo-interstitial fibrosis. Her second renal biopsy performed 5 years after MFT demonstrated decreased mesangial matrix/glomerulus ratio (42.0+/-4.0% to 29.2+/-1.9% [mean+/-S.D.], p<0.001) and increased her number of glomerular capillaries lumen per glomerulus (47+/-11 to 77+/-12, p<0.006). The number of vascular endothelial growth factor (VEGF)-expressing cells in the glomerular capillary significantly increased. Increased tubulo-interstitial fibrosis and the thickness of glomerular basement membrane (GBM) seen in the first biopsy specimen had decreased in the specimen taken at the second biopsy. Our case provides evidence that glomerular morphological improvements including decreased mesangial deposit and VEGF-related vasculogenesis in response to MFT goes along with functional normalization of diabetic nephropathy, which could not be attained in type 1 diabetic patients that underwent pancreas transplantation.
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PMID:Complete remission of diabetic nephropathy in a type 1 diabetic patient with near-nephrotic range proteinuria and reduced renal function. 1916 60

Angiogenesis has become an innovative target in cancer therapy. Agents that inhibit vascular endothelial growth factor (VEGF), one of the most potent promoters of angiogenesis, and its receptor have significant implications for clinical practice. Bevacizumab, sorafenib, sunitinib and other anti-VEGF drugs are frequently complicated by mild proteinuria and hypertension. Other unique renal effects, such as high-grade proteinuria and acute kidney injury, have been described. The most common histopathologic kidney lesion is thrombotic microangiopathy, with other glomerular lesions and interstitial nephritis occurring less frequently. The mechanism for anti-VEGF therapy-induced hypertension is not well understood; however, nitric oxide pathway inhibition, rarefaction, and oxidative stress may be important in its pathogenesis. Glomerular injury may develop from loss of VEGF effect on maintaining the filtration barrier. Adverse effects of anti-VEGF class of drugs are manageable but require close attention and follow-up. Understanding the fundamentals of anti-VEGF drugs' mechanism of action and their clinical implications is crucial when caring for patients receiving anti-VEGF therapy.
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PMID:Renal effects of anti-angiogenesis therapy: update for the internist. 1933 23

Antiangiogenic therapy has now become a cornerstone in the treatment of several solid tumor cancers. Those drugs present with a renal toxicity profile manifesting as proteinuria and hypertension, often reported in the literature to be linked to bevacizumab, a monoclonal antibody targeted at the circulating vascular endothelial growth factor (VEGF). However, there is evidence that those side effects are most probably related to the pharmacological action of those drugs: the inhibition of the VEGF pathway. Thus, they may occur with any antiangiogenic therapy, either those acting on circulating VEGF (bevacizumab or VEGF-trap), or those acting on VEGF receptor(s) (sunitinib, sorafenib, or axitinib). Clinicians should thus be aware of such a 'class effect' to appropriately monitor and treat their patients, regardless of which antiangiogenic drug is used.
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PMID:Hypertension and proteinuria: a class-effect of antiangiogenic therapies. 1934 5

A 65-year-old man was admitted to our hospital with abdominal fullness and leg edema in April 2005. Diabetes mellitus and hypertension that had been diagnosed in 1990 were well-controlled with oral hypoglucemic drug. He presented with malignant thymoma accompanied by multiple metastases in the right thoracic space in December 2000. He was treated with total thymectomy, combined with chemotherapy (cisplatin + vinorelbin) and hyperthermia. This strategy obviously reduced the tumor mass. However, CT scans showed multiple recurrences of thymoma in December 2004 and abdominal fullness and leg edema appeared shortly thereafter. Laboratory findings revealed proteinuria (over 10 g/day), hypoalbuminemia, hyperlipidemia and renal dysfunction. A kidney biopsy revealed minor glomerular abnormality. He was diagnosed with minimal change nephrotic syndrome (MCNS) complicated with the recurrence of malignant thymoma. Corticosteroid therapy was started, but dialysis was transiently required to protect against oliguric acute renal failure. Three weeks after the initiation of steroid therapy, the proteinuria was improved to less than 1.0 g/day and renal function returned to within the normal range. Subsequent corticosteroid combined with immunosuppressive therapy resulted in good control of his nephrotic syndrome (NS) without recurrence. There have been a few case reports showing NS complicated with malignant thymoma. Among these, several cases with MCNS occurred after thymectomy for malignant thymoma. Interestingly, both the thymoma mass and high pre-treatment vascular endothelial growth factor (VEGF) levels decreased as NS improved with steroid therapy. These findings suggest that VEGF also might have been associated with the onset of NS in this patient.
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PMID:[Minimal change nephrotic syndrome complicated with recurrence of malignant thymoma: an interesting case with remission due to steroid therapy of both nephrotic syndrome and thymoma]. 1937 99

A 51-year-old man with immunoglobulin A (IgA) nephropathy developed metastatic renal-cell carcinoma of his native right kidney, 3.5 years post kidney transplant. At that time renal function was stable with the presence of only mild proteinuria. Shortly after chemotherapy with sorafenib [anti-vascular endothelial growth factor (VEGF)] was initiated, progressive renal impairment, hypertension, and nephrotic-range proteinuria developed. Allograft biopsy showed extensive IgA nephropathy. After withdrawal of the anti-VEGF therapy, however, renal function and blood pressure improved, and proteinuria diminished. Based on the clinical course and histopathological findings we hypothesize that sorafenib may induce nephrotic-range proteinuria and renal impairment, possibly through anti-VEGF-mediated effects on the progression of IgA nephropathy.
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PMID:Nephrotic-range proteinuria in a patient with a renal allograft treated with sorafenib for metastatic renal-cell carcinoma. 1938 58

Several novel therapies have been approved recently in advanced renal cell carcinoma (RCC). These agents inhibit pathways downstream of loss of the von Hippel-Lindau gene VHL. They target the vascular endothelial growth factor (VEGF) ligand, VEGF receptor (VEGFR), mammalian target of rapamycin (mTOR), and other potentially important pathways. Even with improvements in survival, disease progresses in all patients. There is a critical need to increase complete responses (now rare). One such strategy is combining several agents to block different levels of the VEGF-VEGFR axis (vertical blockade). Alternatively, combination of a VEGF-VEGFR inhibitor with an mTOR inhibitor is attractive. Finally, horizontal blockade of VEGFR with epidermal growth factor receptor and/or platelet-derived growth factor receptor, all signaling pathways activated by hypoxia-inducible factor, is another approach. Already trials have revealed difficulties with combination therapy. By combining agents, the toxicity of 1 or both can be enhanced. The authors of this article report their experience with sorafenib plus bevacizumab, which produced increases in hand-foot syndrome, hypertension, and proteinuria, all known toxic effects. Clinical activity was impressive with 25 responses in 48 patients (52% response rate). Other combinations also required dose reductions (sorafenib with temsirolimus) or were intolerable (sunitinib with temsirolimus or sunitinib with bevacizumab). Unexpected toxicity characterized by microangiopathic hemolytic anemia occurred late in treatment with sunitinib and bevacizumab. Toxicity may be more severe in patients with RCC, who frequently have 1 kidney and poor renal function. Once tolerability for combination regimens has been established, it will be critical to design informative phase 2 trials and address the benefit of combination versus sequential therapy.
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PMID:Combination targeted therapy in advanced renal cell carcinoma. 1940 58

It is now clearly established that anti-vascular endothelial growth factor (VEGF) drug class induces hypertension and proteinuria sometimes related to thrombotic microangiopathy and/or various glomerulopathies, according to capillary and glomerular VEGF and VEGF-receptor expressions. As reported in the literature, anti-epidermal growth factor receptor (EGFR) therapies seem to be less nephrotoxic. Indeed, many reports of anti-EGFR nephrotoxicity are tubular dependent such as acute tubular necrosis, electrolyte disorders (hypophosphatemia, hypomagnesemia, etc.) or both. This is explained by elective tubular expression of renal EGF/EGFR. In this paper, we focus on electrolyte disorders related to anti-EGFR treatment and discuss the tubular involvement of these drugs based on their renal expression.
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PMID:Electrolyte disorders related to EGFR-targeting drugs. 1940 15


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