UMLS:C0033687 - FACTA Search

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

Numerous murine models of polycystic kidney disease (PKD) have been described. While mouse models are particularly well suited for investigating the molecular pathogenesis of PKD, rats are well established as an experimental model of renal physiologic processes. Han:SPRD-CY: rats have been proposed as a model for human autosomal dominant PKD. A new spontaneous rat mutation, designated wpk, has now been identified. In the mutants, the renal cystic phenotype resembles human autosomal recessive PKD (ARPKD). This study was designed to characterize the clinical and histopathologic features of wpk/wpk mutants and to map the wpk locus. Homozygous mutants developed nephromegaly, hypertension, proteinuria, impaired urine-concentrating capacity, and uremia, resulting in death at 4 wk of age. Early cysts were present in the nephrogenic zone at embryonic day 19. These were localized, by specific staining and electron microscopy, to differentiated proximal tubules, thick limbs, distal tubules, and collecting ducts. In later stages, the cysts were largely confined to collecting ducts. Although the renal histopathologic features are strikingly similar to those of human ARPKD, wpk/wpk mutants exhibited no evidence of biliary tract abnormalities. The wpk locus maps just proximal to the CY: locus on rat chromosome 5, and complementation studies demonstrated that these loci are not allelic. It is concluded that the clinical and renal histopathologic features of this new rat model strongly resemble those of human ARPKD. Although homology mapping indicates that rat wpk and human ARPKD involve distinct genes, this new rat mutation provides an excellent experimental model to study the molecular pathogenesis and renal pathophysiologic features of recessive PKD.
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PMID:New rat model that phenotypically resembles autosomal recessive polycystic kidney disease. 1109 50

Because proteinuria has been demonstrated in patients with autosomal-dominant polycystic kidney disease (ADPKD), we have investigated whether proteinuria also occurs in the (cy/+) rat, a widely used model for ADPKD. Increased urinary excretion of proteins, in particular of albumin, can be found in 16-wk-old (cy/+) rats, with a gel electrophoresis pattern compatible with a tubular origin of proteinuria. Using FITC-labeled dextran as an in vivo tracer for renal tubular endosomal function, we could show that portions of cyst-lining epithelia from proximal tubules have lost the ability to endocytose, which is necessary for the reabsorption of low-molecular-weight proteins. By immunohistochemistry, the expression of other proteins implicated in endocytosis, such as the chloride channel ClC-5 and the albumin receptor megalin, correlated well with the presence and absence of FITC-dextran in cysts. As an example of growth factor systems possibly being affected by this endocytosis defect, we could detect increased urinary levels of insulin-like growth factor-I protein in (cy/+) animals. These data indicate that proteinuria and albuminuria in the aforementioned rat model for ADPKD are due to a loss of the endocytic machinery in epithelia of proximal tubular cysts. This may also affect the concentration of different growth factors and hormones in cyst fluids and thus modulate cyst development.
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PMID:An endocytosis defect as a possible cause of proteinuria in polycystic kidney disease. 1120

Proteinuria and microalbuminuria occur with a highly variable severity and are associated with progression of autosomal dominant polycystic kidney disease (ADPKD). Dilazep dihydrochloride, an antiplatelet drug, is effective in patients with immunoglobulin A nephropathy or diabetic nephropathy. We studied whether dilazep dihydrochloride affects the urinary albumin excretion (UAE) in normotensive and hypertensive patients with ADPKD. Twelve normotensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 6, group A) and a placebo group (n = 6, group B). In addition, 10 hypertensive ADPKD patients with microalbuminuria were randomly assigned to two groups: a dilazep (300 mg/day) treatment group (n = 5, group C) and a placebo group (n = 5, group D). Treatment with dilazep was continued for a period of 6 months, at the end of which the UAE was reduced form 130 +/- 52 to 46 +/- 26 microg/min (p < 0.01) in group A. There was no reduction in group C. There were no changes in UAE in placebo groups B and D. These results suggest that dilazep dihydrochloride may be effective in reducing UAE in normotensive ADPKD patients with microalbuminuria.
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PMID:Effect of dilazep dihydrochloride on urinary albumin excretion in patients with autosomal dominant polycystic kidney disease. 1134 Mar 55

In autosomal dominant polycystic kidney disease (ADPKD), renal function remains normal for many years into adult life while cysts form and expand progressively, starting in childhood. The longitudinal relationships between renal volume growth, hypertension, and renal function loss have not been examined in detail. At the University of Colorado (Denver, CO), 229 adult subjects with ADPKD participated in a longitudinal study from 1985 to 2001. Sequential ultrasound examinations were performed at a mean interval of 7.8 +/- 3.1 years (range, 2.6 to 15.1 years). Renal volume was calculated using a standard formula for a modified ellipsoid. The Modified Diet in Renal Disease equation was used to calculate glomerular filtration rate (GFR). The mean annual increase in renal volume was 46 +/- 55 cm3, and mean annual decline in GFR was 2.4 +/- 2.8 mL/min/1.73 m2. Men had faster renal growth, more severe hypertension, and a faster decline in GFR than women of similar ages. Multiple linear regression showed a significant relationship between rate of change in GFR and renal volume growth rate, initial renal volume, proteinuria, and age at entry. Correlational analysis showed a significant correlation between GFR and renal volume over time (R = -0.53) and between follow-up renal volume and follow-up GFR (R = -0.50) for both men and women. We conclude that renal volume and rate of renal volume growth may be useful markers for disease progression in early stages of ADPKD when GFR is preserved.
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PMID:Relationship between renal volume growth and renal function in autosomal dominant polycystic kidney disease: a longitudinal study. 1204 22

Clusterin is a secreted glycoprotein that is synthesized after several types of tubular injury. We therefore wondered whether the urinary excretion of clusterin could serve as a parameter to determine the severity of tubular damage. Using an affinity-purified rabbit antiserum raised against recombinant clusterin, we established an enzyme-linked immunosorbent assay to measure the urinary excretion of clusterin after bilateral renal ischemia, in the (cy/ +) rat model of autosomal-dominant polycystic kidney disease and in the FHH rat model of focal segmental glomerulosclerosis. After bilateral renal ischemia, the urinary excretion of clusterin paralleled the excretion of total protein and albumin and correlated with the extent of tubular damage. Male (cy/ +) rats, but not female (cy/ +) rats, excreted more clusterin than age-matched (+/ +) rats, a finding consistent with the more rapid course of the disease in males. FHH rats presented with pronounced proteinuria and albuminuria but did not excrete increased levels of clusterin. Urinary clusterin levels could therefore serve as a valuable marker for the severity of tubular damage. Furthermore, clusterin may also help to differentiate between tubular and glomerular forms of proteinuria.
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PMID:Urinary clusterin levels in the rat correlate with the severity of tubular damage and may help to differentiate between glomerular and tubular injuries. 1245 27

Nephrin and NEPH1, the gene products of NPHS1 and NEPH1, are podocyte membrane proteins of the Ig superfamily. Similar to the nephrin knockout, mice lacking NEPH1 show severe proteinuria leading to perinatal death. To identify the ligand of NEPH1, the extracellular domain of NEPH1 was fused to human IgG. This NEPH1-Ig fusion protein labeled the glomerular capillary wall of mouse kidneys in a staining pattern identical to NEPH1 and nephrin, prompting speculation that that NEPH1 might form homodimers and/or heterodimers with nephrin. In coimmunoprecipitation and pull-down assays, the NEPH1-Ig fusion protein precipitated wild-type NEPH1 from overexpressing HEK 293T cells. Truncational analysis revealed that the adhesive properties were not confined to a single Ig domain of NEPH1. Fusion proteins containing two Ig domains of NEPH1 were sufficient to immobilize NEPH1, but they failed to interact with control protein containing the phylogenetically related PKD repeats of polycystin-1. NEPH1 also precipitated nephrin, a protein with eight Ig domains and a fibronectin-like domain. Truncational analysis of nephrin revealed a very similar mode of interaction, i.e., two nephrin Ig domains fused to human IgG precipitated either nephrin or NEPH1, but not the control protein. Both NEPH1 and nephrin interactions were strictly dependent upon posttranslational glycosylation, and bacterially expressed protein failed to bind NEPH1. These findings demonstrate that the Ig domains of NEPH1 and nephrin form promiscuous homodimeric and heterodimeric interactions that may facilitate cis- and trans- homodimerizations and heterodimerizations of these molecules at the glomerular slit diaphragm.
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PMID:Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1. 1266 Mar 26

Acute renal failure in the newborn is a common problem and is typically classified as prerenal, intrinsic renal disease including vascular insults, and obstructive uropathy. In the newborn, renal failure may have a prenatal onset in congenital diseases such as renal dysplasia with or without obstructive uropathy and in genetic diseases such as autosomal recessive polycystic kidney disease. Acute renal failure in the newborn is also commonly acquired in the postnatal period because of hypoxic ischemic injury and toxic insults. Nephrotoxic acute renal failure in newborns is usually associated with aminoglycoside antibiotics and nonsteroidal anti-inflammatory medications used to close a patent ductus arteriosis. Alterations in renal function occur in approximately 40% of premature newborns who have received indomethacin and such alterations are usually reversible. Renal artery thrombosis and renal vein thrombosis will result in renal failure if bilateral or if either occurs in a solitary kidney. Cortical necrosis is associated with hypoxic/ischemic insults due to perinatal anoxia, placenta abruption and twin-twin or twin-maternal transfusions with resultant activation of the coagulation cascade. As in older children, hospital acquired acute renal failure is newborns is frequently multifactorial in origin. Although the precise incidence and prevalence of acute renal failure in the newborn is unknown, several studies have shown that acute renal failure is common in the neonatal intensive care unit. Recent interesting studies have demonstrated that some newborns may have genetic risks factors for acute renal failure. Once intrinsic renal failure has become established, management of the metabolic complications of acute renal failure continues to involve appropriate management of fluid balance, electrolyte status, acid-base balance, nutrition and the initiation of renal replacement therapy when appropriate. Renal replacement therapy may be provided by peritoneal dialysis, intermittent hemodialysis, or hemofiltration with or without a dialysis circuit. The preferential use of hemofiltration by pediatric nephrologists is increasing while the use of peritoneal dialysis is decreasing except for neonates and small infants. Peritoneal dialysis has been a major modality of therapy for acute renal failure in the neonate when vascular access may be difficult to maintain. In the newborn, the prognosis and recovery from acute renal failure is highly dependent upon the underlying etiology of the acute renal failure. Factors that are associated with mortality include multiorgan failure, hypotension, need for pressors, hemodynamic instability, and need for mechanical ventilation and dialysis. The mortality and morbidity of newborns with acute renal failure is much worse in neonates with multiorgan failure. Newborns who have suffered substantial loss of nephrons as may occur in cortical necrosis are at risk for late development of renal failure after apparent recovery from the initial insult. Similarly, hypoxic/ischemic and nephrotoxic injury to the developing kidney can result is decreased nephron number. Newborns with acute renal failure need life-long monitoring of their renal function, blood pressure, and urinalysis. Typically, the late development of chronic renal failure will first becomes apparent with the development of hypertension, proteinuria, and eventually an elevated blood urea nitrogen and creatinine.
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PMID:Acute renal failure in the newborn. 1520 Feb 50

There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. In 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled "El Proyecto de Enfermedades Renales en Bolivia" (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center "Aldo e Cele Dacco" of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled "First Clinical and Epidemiological Program of Renal Diseases"-under the auspices of the Renal Sister Center Program of the International Society of Nephrology-was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted by 21 clinical centers. Apparently healthy patients (14,082) were enrolled over a period of 7 months. Urinary abnormalities were found on first screening in 4261 patients, but only 1019 patients (23.9%) were available for follow-up. At second urinalysis, 35% of patients had no abnormalities. In the remaining positive group of patients, further investigations disclosed the following abnormalities: urinary tract infection (48.4%), isolated hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%), and other diagnoses 4.3% (kidney stones, 1.3%; diabetic nephropathy, 1%; polycystic kidney diseases, 1.9%). The experience gained from this initial screening program formed the basis for a second study aimed to prevent renal disease progression in a selected Bolivian population with high altitude polycythemia. In conclusion, our studies show that mass screening of the population for renal disease is feasible in developing countries and can provide useful information on frequency of renal diseases. Also, in patients with altitude polycythemia, long-term treatment with low doses of enalapril safely prevents increase in arterial blood pressure and progressively reduces hematocrit and proteinuria. Aside from its scientific value, this last study can be taken as an example of how, by rationalizing resources and investing in research programs, renal disease progression and cardiovascular risk may eventually improve, which ultimately should translate into less demand for dialysis, and thus provide alternatives to costly RRT. The transformation of the Bolivian pilot model into a systematic program applicable to most emerging countries may be seen as a task of national nephrology societies, along with methodologic and economic support of international bodies.
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PMID:Strategies for national health care systems in emerging countries: the case of screening and prevention of renal disease progression in Bolivia. 1601 7

The epithelial tight junction (TJ) has three major functions. As a "gate," it serves as a regulatory barrier separating and maintaining biological fluid compartments of different composition. As a "fence," it generates and maintains the apicobasal polarity of cells that form the confluent epithelium. Finally, the TJ proteins form a trafficking and signaling platform that regulates cell growth, proliferation, differentiation, and dedifferentiation. Six examples are selected that illustrate the emerging link between TJ dysfunction and kidney disease. First, the glomerular slit diaphragm (GSD) is evolved, in part, from the TJ and, on maturation, exhibits all three functions of the TJ. GSD dysfunction leads to proteinuria and, in some instances, podocyte dedifferentiation and proliferation. Second, accumulating evidence supports epithelial-mesenchymal transformation (EMT) as a major player in renal fibrosis, the final common pathway that leads to end-stage renal failure. EMT is characterized by a loss of cell-cell contact and apicobasal polarity, which are hallmarks of TJ dysfunction. Third, in autosomal dominant polycystic kidney disease, mutations of the polycystins may disrupt their known interactions with the apical junction complex, of which the TJ is a major component. This can lead to disturbances in epithelial polarity regulation with consequent abnormal tubulogenesis and cyst formation. Fourth, evidence for epithelial barrier and polarity dysregulation in the pathogenesis of ischemic acute renal failure will be summarized. Fifth, the association between mutations of paracellin-1, the first TJ channel identified, and clinical disorders of magnesium and calcium wasting and bovine renal fibrosis will be used to highlight an integral TJ protein that can serve multiple TJ functions. Finally, the role of WNK4 protein kinase in shunting chloride across the TJ of the distal nephron will be addressed.
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PMID:Tight junction biology and kidney dysfunction. 1633 62

Polycystic kidney disease (PKD) is associated with mutations in PKD1 and PKD2 and vascular abnormalities. The links between the epithelial and vascular defects, however, are poorly understood. Vascular endothelial growth factor (VEGF) has been shown to be critical for normal kidney development. In animal models, blockade of VEGF in the perinatal period can lead to abnormal glomerular development, impaired nephrogenesis, proteinuria, and renal failure. We hypothesized that brief blockade of VEGF signaling during early postnatal kidney development can lead to renal cyst development. On days 2 and 4 of life, CD-1 mice were treated with antibodies generated against the extracellular portion of the VEGF receptor 2 (DC101), the area of the receptor where VEGF binding occurs. Mice developed renal cysts between 2 and 3 weeks. The DC101-treated mice also had increased cell proliferation in the renal tubule epithelium. In addition, mice receiving DC101 developed abnormal glomeruli, proteinuria, and patchy cellular infiltrates. Early disruption of VEGFR-2 signaling during the perinatal period results in renal cyst formation, impaired glomerulogenesis, and inflammation. VEGF could be a key link between vascular and cystic changes in kidney cyst formation.
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PMID:VEGF receptor 2 blockade leads to renal cyst formation in mice. 1657 16

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