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)

A nephropathy with severe tubular atrophy was observed in Beagle dogs after oral administration of K2HPO4 for 14 or 38 weeks. We describe the complete lysosomal degradation of atrophying tubular epithelial cells. During two experiments of 14 and 38 weeks duration, respectively, a total of 15 Beagle dogs received 0.8 g K2HPO4/kg body weight daily with their food. All dogs were examined clinically at regular intervals. Renal biopsies were taken in the fourth week from beagles of the 14-week study. Results were compared with those of control dogs. At the end of the experiments the animals were killed and necropsies done. Different stains and histochemical reactions were applied to paraffin sections of the kidneys. Acid phosphatase and beta-glucuronidase were found on cryostat sections. Kidneys fixed by perfusion of five Beagles from the 38-week study and three Beagles of the 14-week study, and from five control dogs, were examined electron microscopically. Ultrahistochemically, acid phosphatase was demonstrated. Clinically, the dogs in both experiments vomited, were cachectic, and had elevated creatinine and blood urea nitrogen. Morphologically, qualitatively identical changes were seen, but the renal damage was most marked at 38 weeks. There were disseminated tubular atrophy (usually of the proximal tubules), focal scar tissue and nephrocalcinosis. The following pathogenesis was established for the lesions of the proximal tubule: Tubular atrophy begins with loss of differentiation of epithelial cells. Enzyme histochemistry, ultrahistochemistry and electron microscopy show an increase in autophagic vacuoles and autophagolysosomes. The lysosomal bodies showing fusion enclose large parts of the cytoplasm as the process continues. Complete lysosomal degradation of epithelial cells and extrusion of large lysosomes into the tubular lumen follow. After complete enzymatic digestion of the intratubular detritus, the residue is empty, convoluted and collapsed tubular basement membrane. Atrophic tubular epithelial cells have many organelle-free zones at their base, which contain fine filamentous material resembling that of the basement membrane. The degradation process described here may explain why clinically the urinary sediment contains few cylinders and epithelial cells and why proteinuria decreases significantly toward the end of the experiment. So far, it is not clear whether the tubular basement membrane is synthesized by the tubular cells, by fibroblasts or by both cell types. The presence of basement membrane-like material in tubular epithelial cells and in parietal epithelial cells of the glomerulus favors the view that epithelial cells produce the basement membranes and that increased production of basement membrane-like material is a sign of loss of differentiation.
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PMID:[Potassium hydrogen phosphate induced nephropathy in the dog. I. Pathogenesis of tubular atrophy (author's transl)]. 742 30

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.
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PMID:Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. 770 83

Idiopathic low-molecular-weight (LMW) proteinuria is a newly described renal disease in Japan and Italy. We report on 7 patients who manifested bilateral or unilateral nephrocalcinosis, as demonstrated by abdominal computed tomography scans. Renal histology revealed calcinosis of renal tubules in 2 patients. Computed tomography is a reliable method for the detection of nephrocalcinosis in this disorder. Hypercalciuria was also seen in 6 patients. A calcium-loading test performed in 2 patients suggested that hypercalciuria was of renal origin. Although the true pathogenesis is still not known, hypercalciuria and nephrocalcinosis appear to be a common complication in patients with idiopathic LMW proteinuria. These complications and clinical features suggest that idiopathic LMW proteinuria in Japan is likely to be identical to Dent's disease in the United Kingdom.
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PMID:Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent's disease in United Kingdom? 775 56

The oculocerebrorenal (Lowe) syndrome is an X-linked recessive disorder characterized by congenital cataracts, hypotonia, developmental delay, poor growth and renal tubular dysfunction. Although the disorder has been mapped to chromosome Xq24-26, the underlying metabolic defect remains unknown. The renal component of the Lowe syndrome comprises tubular dysfunction, that is tubular proteinuria and generalized aminoaciduria progressing to the renal Fanconi syndrome, with later glomerular disease. Clinical problems typically include polyuria, acidosis, hypophosphatemia with rickets and eventually end stage renal disease. Hypercalciuria and its sequelae (nephrocalcinosis and nephrolithiasis) have not been described as cardinal features of the untreated disorder although they reportedly complicate vitamin D and calcium therapy of rickets. We discuss 5 boys with congenital cataracts, hypotonia, developmental delay, failure to thrive and the renal Fanconi syndrome who were diagnosed with the Lowe syndrome and in whom hypercalciuria was documented at diagnosis. We conclude that hypercalciuria and its sequelae may occur commonly in patients with the Lowe syndrome as a component of tubular dysfunction or a complication of therapy.
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PMID:Hypercalciuria and nephrocalcinosis in the oculocerebrorenal syndrome. 786 19

Dent's disease, an X-linked renal tubular disorder, is a form of Fanconi syndrome which is characterized by proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. Previous studies localised the gene responsible to Xp11.22, within a microdeletion involving the hypervariable locus DXS255. Further analysis using new probes which flank this locus indicate that the deletion is less than 515 kb. A 185 kb YAC containing DXS255 was used to screen a cDNA library from adult kidney in order to isolate coding sequences falling within the deleted region which may be implicated in the disease aetiology. We identified two clones which are evolutionarily conserved, and detect a 9.5 kb transcript which is expressed predominantly in the kidney. Sequence analysis of 780 bp of ORF from the clones suggests that the identified gene, termed hCIC-K2, encodes a new member of the CIC family of voltage-gated chloride channels. Genomic fragments detected by the cDNA clones are completely absent in patients who have an associated microdeletion. On the basis of the expression pattern, proposed function and deletion mapping, hCIC-K2 is a strong candidate for Dent's disease.
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PMID:Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). 787 26

We describe a familial form of renal Fanconi syndrome characterized by hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis and slowly progressive renal failure. Males are much more severely affected than females. The patients studied included 15 males and 10 females, and five families with up to three generations involved. Studies of the two largest families described here have already shown that their disease is inherited on the X-chromosome. The series contains the two unrelated patients originally described by Dent and Friedman in 1964 as 'hypercalcuric rickets'.
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PMID:Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. 792 1

Dent's disease is a familial proximal renal tubular disorder which is associated with low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones and renal failure. The mode of inheritance and the primary defect for this disorder are unknown. An analysis of 5 unrelated British families revealed a greater disease severity in males and an absence of male to male transmission. This suggested an X-linked inheritance and we investigated this further by linkage studies in 33 members (12 affected, 21 unaffected) from two 3-generation families. Twenty X-linked polymorphic markers were used and linkage was established with the Xp11 loci ARAFI, DXS426, DXS255 and DXS988 with peak LOD scores and recombination fractions (theta) of 5.42 (theta = 0.000), 3.61 (theta = 0.000), 5.48 (theta = 0.000) and 4.25 (theta = 0.045) respectively. In addition, DXS255 revealed a microdeletion in the affected members of one family, thereby further localising Dent's disease to Xp11.22. Combined multilocus linkage analysis and deletion mapping studies defined the locus order Xpter-MAOB-(ARAFI, DXS426)-SYP-TFE3-(DXS255, DENT'S)-DXS988-Xcen, thereby mapping the microdeletion associated with Dent's disease to a 4 centiMorgan interval flanked by TFE3 and DXS988. Thus, Dent's disease is an X-linked disorder which is associated with a microdeletion of Xp11.22, and a further characterisation of this gene will help to elucidate the factors controlling proximal renal tubular function and the development of kidney stones.
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PMID:Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. 811 83

Dent disease, an X-linked familial renal tubular disorder, is a form of Fanconi syndrome associated with proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, and eventual renal failure. We have previously used positional cloning to identify the 3' part of a novel kidney-specific gene (initially termed hClC-K2, but now referred to as CLCN5), which is deleted in patients from one pedigree segregating Dent disease. Mutations that disrupt this gene have been identified in other patients with this disorder. Here we describe the isolation and characterization of the complete open reading frame of the human CLCN5 gene, which is predicted to encode a protein of 746 amino acids, with significant homology to all known members of the ClC family of voltage-gated chloride channels. CLCN5 belongs to a distinct branch of this family, which also includes the recently identified genes CLCN3 and CLCN4. We have shown that the coding region of CLCN5 is organized into 12 exons, spanning 25-30 kb of genomic DNA, and have determined the sequence of each exon-intron boundary. The elucidation of the coding sequence and exon-intron organization of CLCN5 will both expedite the evaluation of structure/function relationships of these ion channels and facilitate the screening of other patients with renal tubular dysfunction for mutations at this locus.
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PMID:Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). 857 51

The annual urinary screening of Japanese children above 3 yr of age has identified a progressive proximal renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. The disorder, which has a familial predisposition and occurs predominantly in males, has similarities to three X-linked proximal renal tubular disorders that are due to mutations in the renal chloride channel gene, CLCN5. We have investigated four unrelated Japanese kindreds with this tubulopathy and have identified four different CLCN5 mutations (two nonsense, one missense, and one frameshift). These are predicted to lead to a loss of chloride channel function, and heterologous expression of the missense CLCN5 mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wild-type. In addition, single-stranded conformation polymorphism (SSCP) analysis was found to be a sensitive and specific mutational screening method that detected > 75% of CLCN5 mutations. Thus, the results of our study expand the spectrum of clinical phenotypes associated with CLCN5 mutations to include this proximal renal tubular disorder of Japanese children. In addition, the mutational screening of CLCN5 by SSCP will help to supplement the clinical evaluation of the annual urinary screening program for this disorder.
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PMID:Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). 906 55

The annual urinary screening of Japanese children above three years of age has identified a progressive renal tubular disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. The disorder has been observed in over 60 patients and has a familial predisposition. Mutations of a renal chloride channel gene, CLCN5, have been reported in four such families, and we have undertaken studies in additional patients from 10 unrelated, non-consanguineous Japanese families to further characterize such CLCN5 mutations and to ascertain their prevalence. CLCN5 abnormalities we identified in 7 of the 10 unrelated patients and consisted of 5 mutations (2 nonsense, 1 frameshift and 2 missense), 1 deletion and 1 silent polymorphism. A clustering of these mutations in CLCN5 exons 8 and 10 was observed. Over 80% of the CLCN5 mutations could be readily detected by single stranded conformational polymorphism (SSCP) analysis, thereby providing a useful mutation screening method. Our results, which indicate that over 70% of Japanese patients with this renal tubulopathy have CLCN5 mutations, will help in the genetic and clinical evaluation of children at risk from this disorder.
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PMID:Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. 932 29


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