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 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal failure is a frequent and costly complication of many chronic diseases, including diabetes and hypertension. One common feature of renal failure is glomerulosclerosis, the pathobiology of which is unclear. To help elucidate this, we generated a mouse strain carrying the missense mutation Wt1 R394W, which predisposes humans to glomerulosclerosis and early-onset renal failure (Denys-Drash syndrome [DDS]). Kidney development was normal in Wt1(+/R394W) heterozygotes. However, by 4 months of age 100% of male heterozygotes displayed proteinuria and glomerulosclerosis characteristic of DDS patients. This phenotype was observed in an MF1 background but not in a mixed B6/129 background, suggestive of the action of a strain-specific modifying gene(s). WT1 encodes a nuclear transcription factor, and the R394W mutation is known to impair this function. Therefore, to investigate the mechanism of Wt1 R394W-induced renal failure, the expression of genes whose deletion leads to glomerulosclerosis (NPHS1, NPHS2, and CD2AP) was quantitated. In mutant kidneys, NPHS1 and NPHS2 were only moderately downregulated (25 to 30%) at birth but not at 2 or 4 months. Expression of CD2AP was not changed at birth but was significantly upregulated at 2 and 4 months. Podocalyxin was downregulated by 20% in newborn kidneys but not in kidneys at later ages. Two other genes implicated in glomerulosclerosis, TGFB1 and IGF1, were upregulated at 2 months and at 2 and 4 months, respectively. It is not clear whether the significant alterations in gene expression are a cause or a consequence of the disease process. However, the data do suggest that Wt1 R394W-induced glomerulosclerosis may be independent of downregulation of the genes for NPHS1, NPHS2, CD2AP, and podocalyxin and may involve other genes yet to be implicated in renal failure. The Wt1(R394W) mouse recapitulates the pathology and disease progression observed in patients carrying the same mutation, and the mutation is completely penetrant in male animals. Thus, it will be a powerful and biologically relevant model for investigating the pathobiology of the earliest events in glomerulosclerosis.
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PMID:The Wt1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys-Drash syndrome. 1550 92

Metanephric adenomas are benign tumors frequently found post-mortem (from 7% to 22% of autopsies) which originate from distal tubules; they are generally small in dimensions (smaller than 1 cm) and located in the renal cortex. Etiology is unknown, even though they could be associated with smoke, tubular nephrosclerosis, dialysis. An endocrinal relationship was proposed, because of its more frequent incidence in female (2:1). Metanephric adenoma is an uncommon kind of renal adenoma with no malignant potentiality: from the clinical and diagnostic viewpoint its own greater importance depends on the probability of diagnostic misunderstanding with Wilms' tumor; furthermore its echographic, tomographic and arteriographic characteristics are often similar to small renal adenocarcinoma ones (100). Polycytemia is frequently associated to metanephric adenoma as paraneoplastic syndrome and, more rarely, abdominal mass, abdominal pain, hematuria and hypertension (140). The most important study on metanephric adenoma is the one realized by E.K. Mostofi, including 50 cases from the Department of Genitourinary Pathology, Armed Forces Institute of Pathology, Washington, D.C., published in 1995; in this study half of findings was incidental; mean dimension of tumor about 5,5 cm and in 50% it could be seen a distinct capsule sourrounding the tumor (in the remaining cases the capsule was discontinuos or absent) (210). An important radiological characteristic is that metanephric adenomas are more frequent calcificated than other histotypes and, from the pathological viewpoint, the most important differential element seems to be the smaller dimensions of its cells with hyperchromatic nuclei in the absence or lack in mitotic activity and in the absence of chromosome aberrations. In the case of difficult histological diagnosis, cytogenetic and immunohistochemical analysis can be useful. In conclusion, because it is impossible to distinguish in the preoperatory between the metaneprhic adenomas and the other tumoral types on the bases of the symptoms, dimensions or radiographic appearance, it is mandatory to treat it as malignant eteroformations in a therapeutical strategy, when it is possible.
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PMID:Metanephric adenoma: case report and review of the literature. 1556 3

Podocyte loss contributes to the development of glomerulosclerosis. Although podocyte detachment has been recognized as a new mechanism of podocyte loss in glomerular diseases, its time course and relationship to disease activity are not known. Urinary excretion of viable podocytes was quantified in two models of transient glomerular injury, i.e., rats with puromycin aminonucleoside-induced nephrosis (PAN) and mesangioproliferative nephropathy (anti-Thy 1.1 nephritis model), as well as in a model of continuous glomerular injury, i.e., hypertensive nephropathy (5/6-nephrectomy model), and in aging rats. The number of glomerular Wilm's tumor (WT)-1-positive podocytes and the glomerular expression of cell-cycle proteins in vivo were assessed. Urinary podocyte loss occurred in both primary (PAN) and secondary (anti-Thy 1.1 nephritis) in parallel to the onset of proteinuria. However, subsequently proteinuria persisted despite remission of podocyturia. In continuous glomerular injury, i.e., after 5/6-nephrectomy, podocyturia paralleled the course of proteinuria and of systemic hypertension, whereas no podocyturia became detectable during normal aging (up to 12 mo). Despite podocyte detachment of varying degrees, no decrease in glomerular podocyte counts (i.e., WT-1 positive nuclei) was noted in either disease model. Podocyturia in the PAN and anti-Thy 1.1 nephritis model was preceded by entry of glomerular podocytes into the cell cycle, i.e., cyclin D1, cdc2, and/or proliferating cell nuclear antigen (PCNA) expression. Podocyturia is a widespread phenomenon in glomerular disease and not simply a reflection of proteinuria because it is limited to phases of ongoing glomerular injury. The data suggest that podocyturia may become a more sensitive means to assess the activity of glomerular damage than proteinuria.
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PMID:Urinary podocyte loss is a more specific marker of ongoing glomerular damage than proteinuria. 1582 8

Changes in podocyte number or density have been suggested to play an important role in renal disease progression. Here, we investigated the temporal relationship between glomerular podocyte number and development of proteinuria and glomerulosclerosis in the male Munich Wistar Fromter (MWF) rat. We also assessed whether changes in podocyte number affect podocyte function and focused specifically on the slit diaphragm-associated protein nephrin. Age-matched Wistar rats were used as controls. Estimation of podocyte number per glomerulus was determined by digital morphometry of WT1-positive cells. MWF rats developed moderate hypertension, massive proteinuria, and glomerulosclerosis with age. Glomerular hypertrophy was already observed at 10 weeks of age and progressively increased thereafter. By contrast, mean podocyte number per glomerulus was lower than normal in young animals and further decreased with time. As a consequence, the capillary tuft volume per podocyte was more than threefold increased in older rats. Electron microscopy showed important changes in podocyte structure of MWF rats, with expansion of podocyte bodies surrounding glomerular filtration membrane. Glomerular nephrin expression was markedly altered in MWF rats and inversely correlated with both podocyte loss and proteinuria. Our findings suggest that reduction in podocyte number is an important determinant of podocyte dysfunction and progressive impairment of the glomerular permselectivity that lead to the development of massive proteinuria and ultimately to renal scarring.
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PMID:Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury. 1640 8

Hypertension is a frequent problem in children with renal tumour, yet there are few reports from centres in the third world. A retrospective study of blood pressure in a cohort of 46 patients with renal tumours seen over a 3-year period was carried out. Fifty percent of patients presenting with Wilms' tumour were hypertensive. Serum concentrations of active renin correlated poorly with blood pressure. There was no correlation between serum concentrations of active renin and tumour mass or histology. Specific antihypertensive therapy was offered to 11 patients who had either neurological or cardiac complications of hypertension. All other patients with Wilms' tumour had their blood pressure controlled by neoadjuvant chemotherapy. Patients with mesoblastic nephroma were managed by primary surgery. Patients with asymptomatic hypertension may be monitored as hypertension will resolve with neoadjuvant chemotherapy. Those with compelling symptomatology will require additional hypertensive medication.
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PMID:Hypertension in a cohort of African children with renal tumours. 1642 3

The genetics of renal tumors in children is widely recognized. However, most of the studies published to date emphasize the association between Wilms tumor and the WT-1 gene. Recently, a unique translocation between the X chromosome and chromosome 1 or t(X;1) has been described in several reports of renal cell carcinomas (RCCs) diagnosed in children and adolescents that results in PRCC-TFE3 gene fusion. We report here a 9-year old African-American boy with a history of a right congenital mesoblastic nephroma treated with nephrectomy and followed by annual checkups. After 9 years, he was diagnosed with a mass at the hilum of the left kidney during the work-up of new-onset hypertension. A limited biopsy revealed densely hyalinized connective tissue that was initially interpreted to be a hyalinized contralateral mesoblastic nephroma. The child received chemotherapy, but the mass continued to grow. He underwent a left nephrectomy, and the pathology was diagnostic for a clear cell RCC. Chromosomal analysis disclosed a t(X;1)(p11.2;q21) translocation, which is known to result in a PRCC-TFE3 gene fusion. The tumor showed nuclear labeling for TFE3 protein by immunohistochemistry, supporting the above diagnosis. He has been on hemodialysis, is tumor free, and has not been receiving chemotherapy for 24 months. This is the first report of a RCC as a second malignant neoplasm in a child treated for a congenital mesoblastic nephroma.
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PMID:PRCC-TFE3 renal cell carcinoma in a boy with a history of contralateral mesoblastic nephroma. 1680 66

Congenital mesoblastic nephroma (CMN) is a rare tumour of infancy having an overall good prognosis. The less common, atypical CMNs have cellular elements in them and tend to have an unpredictable course. Occurrence in the perinatal period may further change the outcome. By reporting three patients presenting in the perinatal period with atypical CMN, an attempt is made in this paper to characterize the clinical behaviour of these variant tumours. Though one of our patients had an uneventful course, the other two had several complications including polyhydramnios, prematurity, hypertension, haemodynamic instability and tumour spillage. The course was complicated by recurrence in the latter two and refractoriness to chemotherapy and death in one. That the atypical subset of CMNs occurring in the perinatal period can have a stormy course is well illustrated by this report. Possible prognostic factors are evaluated and the sparse reports of similar cases in the literature are reviewed and compared.
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PMID:Atypical congenital mesoblastic nephroma presenting in the perinatal period. 1709 92

HIV-associated nephropathy (HIVAN) is characterized by a collapsed glomerular capillary tuft with hyperplasia and hypertrophy of podocytes. Recently generated were conditional transgenic mice (podocin/Vpr) that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and Tet-on system. These transgenic mice developed renal injury similar to HIVAN when treated with doxycycline for 8 to 12 wk. This study demonstrated that nephron reduction by heminephrectomy markedly enhanced phenotypic changes of podocytes and led to severe FSGS within 4 wk. Nephrotic-range proteinuria was observed already at 2 wk, together with dedifferentiation and dysregulation of podocytes, indicated by decreased expression of nephrin, synaptopodin, and Wilms' tumor 1 protein and increased expression of Ki-67. The acceleration of phenotypic changes of podocytes, proteinuria, and subsequent glomerulosclerosis by heminephrectomy was almost completely inhibited by angiotensin II type 1 receptor (AT1R) blocker olmesartan. In contrast, the renoprotective effect of the calcium channel antagonist azelnidipine was minimal, although it lowered systemic BP to the same level as olmesartan, demonstrating that the inhibitory effect of AT1R blocker was independent of systemic BP. Olmesartan also reduced proteinuria and prevented glomerulosclerosis even by the delayed treatment, which was initiated after the podocyte injury appeared. These data suggest that nephron reduction exaggerates podocyte injury and subsequent glomerulosclerosis, possibly through glomerular hypertension, in the mouse model of HIVAN. AT1R blockade could be beneficial in the treatment of HIVAN by ameliorating podocyte injury by avoiding the vicious cycle of nephron reduction and glomerular hypertension.
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PMID:Angiotensin II type 1 receptor blockade inhibits the development and progression of HIV-associated nephropathy in a mouse model. 1722 13

Congenital abnormalities of the kidney and urinary tract (CAKUT) occur in 1 out of 500 newborns, and constitute approximately 20-30% of all anomalies identified in the prenatal period. CAKUT has a major role in renal failure, and there is increasing evidence that certain abnormalities predispose to the development of hypertension and cardiovascular disease in adult life. Moreover, defects in nephron formation can predispose to Wilms tumour, the most frequent solid tumour in children. To understand the basis of human renal diseases, it is essential to consider how the kidney develops.
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PMID:Renal abnormalities and their developmental origin. 1787 95

Treatment of hypertension depends on the cause and severity of hypertension, and wether it is acute or chronic hypertension. In hypertensive emergencies, antihypertensive therapy should be started immediately, even if the cause of the disease is unknown. If the hypertension is present for a short time, blood pressure could be normalized quickly, but if the hypertension is of long or unknown lasting, blood pressure should be normalized gradually, so in that way blood pressure is normalized in 2 to 4 days. In long-term antihypertensive therapy as little as possible drugs should be used, preferably in one or two daily doses. Depending on etiology and pathophysiology of hypertension, we use following drugs, alone or in combination: beta adrenergic blockers (atenolol, propranolol), vasodilators (hydralazine, minoxidil), ACE inhibitors (captopril, enalapril), calcium-channel blockers (nifedipine), diuretics (hydrochlorthiazide, frusemide) and alpha adrenergic blockers (prazosin, phenoxybenzamine). Recently, ACE inhibitors or calcium-channel blockers have been used as the first step in antihypertensive therapy. Surgical treatment includes elimination of tumors (Wilms tu, pheochromocytoma), coarctation of the aorta, revascularisation or percutaneous angioplasty (stenosis of renal artery) and parcial or unilateral nephrectomy in renal scarring. Nonpharmacological management: weight reduction, physical conditioning, dietary modifications etc. accompany pharmacological therapy in children with moderate-to-severe hypertension and are commonly recognized strategies to control mild elevations of blood pressure in children.
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PMID:[Management of hypertension in children]. 1797 48


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