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Biomedical subjects

C E Kashtan

Publications and source records attributed to C E Kashtan.

At least 19 recordsLinked to original sources
PubMed2000

Expression of the alpha6 chain of type IV collagen in glomerular basement membranes of healthy adult dogs.

OBJECTIVE: To evaluate expression of the alpha6 chain of type IV collagen in the glomerular basement membranes (GBM) of healthy dogs. SAMPLE POPULATION: Kidney specimens from 12 healthy dogs. For comparison, kidney specimens from 8 human subjects between 25 and 83 years old also were evaluated. PROCEDURE: Sections were immunolabeled with a monospecific antibody that cross-reacts with human and canine alpha6(IV) chains and examined by means of fluorescence microscopy. RESULTS: Immunolabeling of the alpha6(IV) chain was not observed in GBM of 6 dogs < or = 30 months old but was observed in GBM of the remaining 6 dogs, all of which were > or = 45 months old. Expression of the alpha6(IV) chain was not observed in GBM of the human subjects, regardless of the age of the subject. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that the alpha6(IV) chain is expressed in GBM of healthy dogs, but the expression is age-dependent. Composition and structural organization of type IV collagen in the GBM of healthy adult dogs is different from that described for other species.

Adult↗
PubMed1999

Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome.

Renal-Coloboma syndrome, an autosomal dominant disorder characterized by colobomatous eye defects, vesicoureteral reflux, and abnormal kidneys, results from mutations in PAX2. The purpose of this study was to identify mutations in PAX2 and understand the associated patient phenotypes. We report a severely affected girl and a mildly affected mother and daughter, all of whom have PAX2 homoguanine tract (7 G) missense mutations. The mother and daughter have optic nerve colobomas and the daughter has vesicoureteral reflux. The severely affected girl developed renal failure and has bilateral colobomatous eye defects. Additionally, this girl developed hydrocephalus associated with platybasia and a Chiari 1 malformation. We examined genomic DNA from these individuals by SSCP and sequencing. The mother and daughter had a novel mutation: a contraction in a string of 7 G's to 6 G's in one allele of PAX2, leading to a premature stop codon two amino acids downstream. The severely affected girl had an expansion to 8 G's, leading to a premature stop codon 27 amino acids downstream. The 8 G expansion has been found in other patients without brain anomalies and has occurred spontaneously in a mouse model, PAX2(1Neu). We expand the known phenotype associated with mutations in PAX2 to include brain malformations. The homoguanine tract in PAX2 is a hot spot for spontaneous expansion or contraction mutations and demonstrates the importance of homonucleotide tract mutations in human malformation syndromes.

Abnormalities, Multiple↗
PubMed1999

Recurrent bacteremia with enteric pathogens in recessive polycystic kidney disease.

Eight children with autosomal recessive polycystic kidney disease (ARPKD) and recurrent bacteremia with enteric pathogens are described. Typical clinical features of bacterial cholangitis were absent, although in five patients histological and/or microbiological data indicated that the bacteremic episodes originated in the biliary tree. Bacteremia with enteric pathogens or recurrent culture-negative febrile illness in a child with ARPKD should raise suspicion of cholangitis, even in the absence of typical clinical findings.

Bacteremia↗
PubMed1999

Aortic dissection in young patients with chronic hypertension.

We describe four patients aged 14 to 21 years who developed acute aortic dissection. In three of the four patients, the course was fatal, despite aggressive medical and surgical intervention. All four patients had sustained systemic hypertension related to chronic renal insufficiency. The patients had no other identifiable risk factors for aortic dissection, including congenital cardiovascular disease, advanced atherosclerosis, vasculitis, trauma, pregnancy, or family history of aortic dissection. Although aortic dissection is rare in individuals younger than 40 years of age, young patients with sustained systemic hypertension are at increased risk for this serious and often fatal condition. Physicians must be aware of this rare complication of hypertension and consider aortic dissection in the differential diagnosis of unusual chest, abdominal, and back pain in hypertensive children, adolescents, and young adults.

Adolescent↗
PubMed1999

The central role of nuclear factor-kappa B in mesangial cell activation.

BACKGROUND: Nuclear factor-kappa B (NF-kappa B) is a family of transcription factors that is recognized by the kappa B enhancer element. Numerous proinflammatory genes have binding sites for NF-kappa B, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kappa B and mediators of cell activation, it is possible that a disruption of NF-kappa B-activating pathways may effectively influence mesangial cell activation. METHODS: We reviewed available studies related to both NF-kappa B and mesangial cells in order to provide evidence for the role of NF-kappa B in mesangial cell activation. RESULTS: Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kappa B activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kappa B activation to down-regulate the inflammatory response in animal models of renal disease has been recently demonstrated. CONCLUSIONS: These data suggest a pivotal role of NF-kappa B in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kappa B in human renal injury.

Animals↗
PubMed1999

Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal recessive disorder that is caused by mutations in the recently discovered nephrin gene, NPHS1 (AF035835). The disease, which belongs to the Finnish disease heritage, exists predominantly in Finland, but many cases have been observed elsewhere in Europe and North America. The nephrin gene consists of 29 exons spanning 26 kb in the chromosomal region 19q13.1. In the present study, the genomic structure of the nephrin gene was analyzed, and 35 NPHS1 patients were screened for the presence of mutations in the gene. A total of 32 novel mutations, including deletions; insertions; nonsense, missense, and splicing mutations; and two common polymorphisms were found. Only two Swedish and four Finnish patients had the typical Finnish mutations: a 2-bp deletion in exon 2 (Finmajor) or a nonsense mutation in exon 26 (Finminor). In seven cases, no mutations were found in the coding region of the NPHS1 gene or in the immediate 5'-flanking region. These patients may have mutations elsewhere in the promoter, in intron areas, or in a gene encoding another protein that interacts with nephrin.

Amino Acid Sequence↗
PubMed1999

Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes.

Alport syndrome (AS) is a genetically heterogeneous disease arising from mutations in genes coding for basement membrane type IV collagen. About 80% of AS is X-linked, due to mutations in COL4A5, the gene encoding the alpha 5 chain of type IV collagen (alpha 5[IV]). A subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes. Most other patients have autosomal recessive Alport syndrome (ARAS) due to mutations in COL4A3 or COL4A4, which encode the alpha 3(IV) and alpha 4(IV) chains, respectively. Autosomal dominant AS has been mapped to chromosome 2 in the region of COL4A3 and COL4A4. The features of AS reflect derangements of basement membrane structure and function resulting from changes in type IV collagen expression. The primary pathologic event appears to be the loss from basement membranes of a type IV collagen network composed of alpha 3, alpha 4, and alpha 5(IV) chains. While this network is not critical for normal glomerulogenesis, its absence appears to provoke the overexpression of other extracellular matrix proteins, such as the alpha 1 and alpha 2(IV) chains, in glomerular basement membranes, leading to glomerulosclerosis. The diagnosis of AS still relies heavily on histologic studies, although routine application of molecular genetic diagnosis will probably be available in the future. Absence of epidermal basement membrane expression of alpha 5(IV) is diagnostic of XLAS, so in some cases kidney biopsy may not be necessary for diagnosis. Analysis of renal expression of alpha 3(IV)-alpha 5(IV) chains may be a useful adjunct to routine renal biopsy studies, especially when ultrastructural changes in the GBM are ambiguous. There are no specific therapies for AS. Spontaneous and engineered animal models are being used to study genetic and pharmacologic therapies. Renal transplantation for AS is usually very successful. Occasional patients develop anti-GBM nephritis of the allograft, almost always resulting in graft loss.

Animals↗
PubMed1999

New form of X-linked dominant hereditary nephritis in dogs.

OBJECTIVE: To determine features of a new form of hereditary nephritis (HN) in dogs. ANIMALS: Parents and 16 first-generation offspring (8 males, 8 females). PROCEDURE: Adolescent dogs that developed renal failure were euthanatized and necropsied. Unaffected dogs were monitored until they were at least 2 years old. Studies included light and electron microscopy of kidneys obtained from affected and unaffected dogs and immunolabeling for collagen-IV chains in renal and epidermal basement membranes (BM). The nucleotide sequence of a portion of exon 35 of the COL4A5 gene was determined in genomic DNA isolated from affected and unaffected males. RESULTS: 7 of 8 male and 2 of 8 female offspring had proteinuria and juvenile-onset chronic renal failure, which progressed more rapidly in the males. Labeling for alpha3-alpha6(IV) chains was completely absent in renal BM of affected males and segmentally absent in affected females. Expression of alpha1-alpha2(IV) chains in glomerular BM (GBM) of affected dogs was increased. Labeling for alpha5-alpha6(IV) chains in epidermal BM was absent in affected males and segmental in affected females. Ultrastructural changes characteristic of HN were observed in GBM of affected dogs. The sequence of exon 35 of COL4A5 was normal in affected dogs. CONCLUSIONS: This renal disease is an example of X-linked dominant HN, with typical abnormalities of GBM ultrastructure and alpha(IV) chain expression. CLINICAL RELEVANCE AND IMPLICATIONS FOR HUMAN MEDICINE: Dogs with this naturally acquired progressive renal disease can be used to investigate the pathogenesis and treatment of similar disorders in human beings and dogs.

Animals↗
PubMed1999

Glomerular disease.

This review focuses on recent insights into the genetics and pathogenesis of several inherited glomerular diseases. Investigation of these disorders has resulted in the identification of proteins that play important roles in glomerular development, structure, and function.

Animals↗
PubMed1998

Chronology of renal scarring in males with Alport syndrome.

We investigated the onset of renal scarring in 62 males (aged 4-26 years) with Alport syndrome by measuring cortical interstitial volume fraction [Vv (interstitium/cortex)] and percentage global glomerular sclerosis in kidney biopsies. Male pediatric (n = 9) and adult (n = 7) donor kidneys served as controls. Creatinine clearance at the time of biopsy was available for 43 Alport patients. A statistically insignificant correlation between age and Vv (interstitium/cortex) was observed in normal subjects (r = +0.47, slope = 0.0009, P = 0.07). In the Alport patients, age was significantly correlated with Vv (interstitium/cortex (r = +0.49, slope = 0.01, P = 0.001) and global glomerular sclerosis (r = +0.41, P = 0.01), and inversely correlated with creatinine clearance (r = -0.33, P = 0.04). Creatinine clearance was inversely correlated with Vv (interstitium/cortex) (r = -0.78, P = 0.001) and global glomerular sclerosis (r = -0.74, P = 0.001). The correlation with creatinine clearance was especially strong for Vv (interstitium/cortex) values above the normal range, i.e., > 0.2 (r = -0.82, P = 0.001), and was absent for Vv (interstitium/cortex) < 0.2 (r = -0.119, P = 0.55). Creatinine clearance values less than 80 ml/min per 1.73 m2 occurred more frequently in patients with Vv (interstitium/cortex) values > 0.2 (P < 0.0001) and in patients with > 10% globally sclerosed glomeruli (P < 0.001). Patients < or = or > 10 years of age differed in Vv (interstitium/cortex) [0.13 +/- 0.09 (mean +/- SD) vs. 0.24 +/- 0.026, P < 0.001], the frequency of Vv (interstitium/cortex) > 0.2 (3/32 vs. 15/31, P < 0.0001), the frequency of > 10% globally sclerosed glomeruli (3/33 vs. 11/30, P < 0.05), mean creatinine clearance (113 +/- 7 vs. 84 +/- 10 ml/min per 1.73 m2, P = 0.057), and the frequency of creatinine clearance < 80 ml/min per 1.73 m2 (1/20 vs. 11/23, P < 0.01). Thus, reduced creatinine clearance in males with Alport syndrome is associated with Vv (interstitium/cortex) > 0.2 and > 10% globally sclerosed glomeruli. These are frequently detectable in the 2nd decade. We hypothesize that most Alport males will require intervention during the 1st decade for optimal preservation of kidney function.

Adolescent↗
PubMed1998

Hemodialysis catheter placement and recirculation in treatment of hyperammonemia.

A 2-year-old girl with carbamoyl phosphate synthetase deficiency underwent emergency hemodialysis (HD) for treatment of acute life-threatening hyperammonemia. HD was performed via catheters placed in each femoral vein serving as vascular access. The tip of one of the catheters (aspirating line) was in the left external iliac vein and the tip of the other catheter (the return line) was in the inferior vena cava (IVC). High blood flow rates were used in order to rapidly lower the blood ammonia (NH3) levels. However, unanticipated marked recirculation in the IVC, between the dialysis aspirating and return catheters, was encountered, preventing significant reduction in blood NH3. The recognition of this problem, suggested solutions, and prevention are described.

Ammonia↗
PubMed1998

X-linked Alport syndrome in females.

Alport syndrome (AS) is in the differential diagnosis of hematuria. Variability in clinical presentation and in the ultrastructural changes of the glomerulus can make the diagnosis of AS a challenge in female patients. The purpose of this report is to present immunostaining for glomerular basement membrane (GBM) expression of alpha5(IV) as an adjunctive diagnostic method. Renal biopsy specimens from eight female patients with clinical presentation suggestive of AS were studied. The patients were between 7 and 36 years of age; six were between 12 and 15 years. Light microscopy and immunohistochemistry using a monoclonal antibody to alpha5(IV) were performed. Controls showed a continuous linear pattern along the GBM in normal kidneys and absence in renal biopsy specimens from male X-linked AS patients. To express the variability of the ultrastructural GBM changes among the patients in the series, we developed a semi-quantitative Alport Index, obtained by quantification of severity and extent of ultrastructural GBM changes. With immunohistochemistry, we showed an interrupted, discontinuous linear pattern for alpha5(IV) in glomeruli from the eight patients in the series, confirming the diagnosis of X-linked AS. The ultrastructural Alport Index varied between 6 and 47, showing the heterogeneity in the severity of the GBM changes, even among the six patients aged between 12 and 15 years. In three of the eight biopsy specimens, the predominant change was thin GBM, and the Alport Index was below 20. Immunohistochemistry for alpha5(IV) in renal biopsy specimens can identify female patients heterozygous for X-linked AS. In this series, the method led to the diagnosis of AS in female patients in whom the predominant ultrastructural change was thin basement membrane.

Adolescent↗
PubMed1998

Expression of mRNA for type IV collagen alpha1, alpha5 and alpha6 chains by cultured dermal fibroblasts from patients with X-linked Alport syndrome.

COL4A5 mutations causing X-linked Alport syndrome (XLAS) are frequently associated with absence of the alpha3, alpha4,alpha5 and alpha6 chains of type IV collagen from basement membranes and increased amounts of the alpha1(IV) and alpha2(IV) chains in glomerular basement membrane. Although many COL4A5 mutations have been described in XLAS, the mechanisms by which these mutations influence the basement membrane appearance of chains other than alpha5(IV) remain poorly understood. In this study, we used dermal fibroblasts from eight normal individuals and nine males with XLAS to test the hypotheses that COL4A5 mutations increase transcription of COL4A1 and suppress transcription of COL4A6. Ribonuclease protection assays revealed that alpha1(IV), alpha5(IV) and alpha6(IV) transcripts were expressed in cultures of dermal fibroblasts. The mRNA levels for alpha1(IV) in eight of nine patients with XLAS were not increased compared to controls; one patient with a large COL4A5 deletion showed significant elevation of alpha1(IV) mRNA levels. No differences in steady-state mRNA levels for alpha6(IV) were found when XLAS fibroblasts were compared with controls, even though little or no alpha6(IV) protein was detectable at the dermal-epidermal junction by immunofluorescence study. This finding suggests that post-transcriptional events account for the absence of alpha6(IV) in the Alport dermal-epidermal junction.

Adolescent↗
PubMed1998

Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome.

Congenital nephrotic syndrome of the Finnish type (NPHS1) is an autosomal-recessive disorder, characterized by massive proteinuria in utero and nephrosis at birth. In this study, the 150 kb critical region of NPHS1 was sequenced, revealing the presence of at least 11 genes, the structures of 5 of which were determined. Four different mutations segregating with the disease were found in one of the genes in NPHS1 patients. The NPHS1 gene product, termed nephrin, is a 1241-residue putative transmembrane protein of the immunoglobulin family of cell adhesion molecules, which by Northern and in situ hybridization was shown to be specifically expressed in renal glomeruli. The results demonstrate a crucial role for this protein in the development or function of the kidney filtration barrier.

Amino Acid Sequence↗
PubMed1998

A model of autosomal recessive Alport syndrome in English cocker spaniel dogs.

BACKGROUND: Dogs with naturally occurring genetic disorders of basement membrane (type IV) collagen may serve as animal models of Alport syndrome. METHODS: An autosomal recessive form of progressive hereditary nephritis (HN) was studied in 10 affected, 3 obligate carrier, and 4 unaffected English cocker spaniel (ECS) dogs. Clinical, pathological, and ultrastructural features of the disease were characterized. Expression of basement membrane (BM) proteins was examined with an immunohistochemical technique using monospecific antibodies. RESULTS: Affected dogs had proteinuria and juvenile-onset chronic renal failure. Glomerular basement membrane (GBM) thickening and multilamellation typical of HN were observed in all renal specimens obtained from proteinuric dogs, and severity of GBM ultrastructural abnormalities varied with the clinical stage of disease. Expression of alpha3(IV) and alpha4(IV) chains was totally absent in the kidney of affected dogs. Expression of alpha5(IV) and a6(IV) chains was normal in Bowman's capsule, collecting tubular BM and epidermal BM of affected dogs. The alpha5(IV) chain was not expressed in distal tubular BM of affected dogs. Expression of alpha5(IV) chains was markedly reduced but not absent, and expression of alpha6(IV) chains was present in GBM of affected dogs. Expression of alpha1-alpha2(IV) chains in GBM of affected dogs was increased. Features of obligate carriers were similar to those of unaffected dogs. CONCLUSIONS: We conclude that HN in ECS dogs is a naturally occurring animal model of autosomal recessive Alport syndrome. However, it differs from human disease in the persistence of alpha5(IV) chains in GBM and in the appearance of a6(IV) chains in GBM.

Animals↗
PubMed1998

Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome?

We describe a family with four members, a mother, two sons, and a daughter, who show clinical features consistent with X linked Alport syndrome. The two males presented with additional features including mental retardation, dysmorphic facies with marked midface hypoplasia, and elliptocytosis. The elliptocytosis was not associated with any detectable abnormalities in red cell membrane proteins; red cell membrane stability and rigidity was normal on ektacytometry. Molecular characterisation suggests a submicroscopic X chromosome deletion encompassing the entire COL4A5 gene. We propose that the additional abnormalities found in the affected males of this family are attributable to deletion or disruption of X linked recessive genes adjacent to the COL4A5 gene and that this constellation of findings may represent a new X linked contiguous gene deletion syndrome.

Abnormalities, Multiple↗