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C E Kashtan

Publications and source records attributed to C E Kashtan.

18 recordsLinked to original sources
PubMed1992

Immunochemical studies of the Alport antigen.

The Alport antigen, a component of normal glomerular basement membranes (GBM) which is absent in Alport familial nephritis, is characterized as a 26 kD non-collagenous (NC1) peptide identified by a monoclonal antibody (Mab A7) and an Alport alloantibody. Both antibodies discriminate X-linkage of the Alport defect using indirect immunofluorescence of hemizygous and heterozygous Alport GBM and epidermal basement membrane (EBM). Immunoblotting of SDS-PAGE gels of collagenase-digested Alport renal BM shows absence of monomeric and dimeric components of the Alport antigen, alpha 3(IV) NC1, and alpha 4(IV) NC1. By immunoprecipitation experiments with specific antibodies, the Alport antigen is distinct from the 26 kD NC1 peptide derived from alpha 1(IV). The monoclonal antibody to the Alport antigen and rabbit antiserum to a non-consensus sequence of alpha 5(IV) NC1 react similarly by immunofluorescence with normal kidney and both fail to bind to Alport renal BM. Two dimension Western blots of collagenase-digested BM show that the anti-Alport antigen and the ant-alpha 5(IV) NC1 react similarly with monomeric and dimeric components of BM collagen. These studies are consistent with the likelihood that the Alport antigen and alpha 5(IV) NC1 are the same or are highly homologous molecules. The precise relationship will require characterization of alpha 5(IV) NC1 protein and determination of the nucleotide sequence of the Alport antigen. The associated absence of alpha 3(IV) NC1 and alpha 4(IV) (NC1) from Alport BM is consistent with other observations for a molecular association of these chains in a novel collagen network.

Antibodies, Monoclonal↗
PubMed1992

Distribution of the alpha 1 and alpha 2 chains of collagen IV and of collagens V and VI in Alport syndrome.

We compared the distribution of the alpha 1 and alpha 2 chains of collagen IV and of collagens V and VI in glomeruli of males with Alport syndrome to their distribution in normal glomeruli and glomeruli from patients with non-Alport renal diseases. alpha 1(IV), alpha 2(IV), collagen V and collagen VI are normally restricted to the mesangium and the subendothelial aspect of the glomerular basement membrane (GBM). In contrast, these proteins were present throughout the entire width of the GBM in Alport glomeruli. These alterations were apparent in "early" Alport glomeruli, that is, those exhibiting minimal abnormalities by light microscopy, and they were further accentuated in sclerosing Alport glomeruli. Obsolescent Alport glomeruli, in which the capillary tuft had collapsed and few remaining cell nuclei were present, exhibited nearly complete loss of alpha 1(IV) and alpha 2(IV), like obsolescent glomeruli in non-Alport diseased kidneys. However, the matrix of obsolescent Alport glomeruli stained intensely for collagen V and collagen VI, while these collagen types were not prominent in obsolescent glomeruli of non-Alport diseases kidneys. These observations suggest that the process of glomerulosclerosis in Alport kidneys has attributes unique to this disease. It would also appear that mutations affecting the Alport gene product have secondary effects on the distribution of other GBM constituents.

Adolescent↗
PubMed1991

Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.

Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.

Acute Kidney Injury↗
PubMed1991

High-density genetic and physical mapping of DNA markers near the X-linked Alport syndrome locus: definition and use of flanking polymorphic markers.

To refine the genetic and physical mapping of the locus for Alport syndrome (ATS), 22 X-chromosome restriction fragment length polymorphism (RFLP) markers that fall between Xq21.3 and Xq25 were tested for genetic linkage with the disease and also mapped with respect to a series of physical breakpoints in this region. The location of the COL4A5 gene, which has recently been shown to be mutated in at least some families with Alport syndrome, was determined with respect to the same physical breakpoints. Two large Utah kindreds were included in the genetic studies, kindreds P and C, with 125 and 63 potentially informative meioses, respectively. Both kindreds have essentially identical nephritis; however, kindred P has sensorineural hearing loss associated with the nephritis, while kindred C does not. A mutation in COL4A5 has been demonstrated for kindred P, but no change in this gene has yet been detected for kindred C. Twelve informative probes did not recombine with the disease locus in either kindred (theta = 0.0, with combined lod scores for the two kindreds ranging from 7.7 to 30.0). The closest markers that could be demonstrated to flank the disease locus were the same for each kindred and thus the locations of the mutations causing the two disease phenotypes are not distinguishable at the current level of genetic resolution. The flanking markers are also useful for the resolution of questionable diagnoses and allow accurate estimates for these families of the rate of sporadic hematuria in noncarrier females (7%) and the penetrance of hematuria for carrier females (93%).

Blotting, Southern↗
PubMed1991

Long-term quality of life after kidney transplantation in childhood.

Transplantation is the treatment of choice for children with end-stage renal disease. However, the long-term quality of life and socioprofessional outcome for those with successful transplants have not previously been reported. We studied these factors in patients transplanted when less than 18 years old who currently have greater than or equal to 10 years of graft function. A total of 57 questionnaires were sent out; 57 (100%) responded [24 female and 33 male patients; average (+/- SD) age at tx = 10 +/- 5 years (0.9-17.7); average f/u = 15.6 +/- 3 years (10-26); current age = 26 +/- 5 years (12-38); 26 had greater than 1 transplant]. Of the 57 respondents, 9 are less than 18 (all are in school); 48 are greater than or equal to 18 (7 in school, 37 employed, 4 unemployed); 12 are married, 1 engaged, and 2 divorced; and 9 have children. While in school, 43 (75%) had participated in sports, 37 (65%) in other extracurricular activities; 7 (12%) were A and 33 (58%) B students; 15 (26%) received awards or scholarships. For those working, the range of occupations is broad (average work week = 41 +/- 5 hr). Health-related absence from work has been nonexistent for 93%. Health is rated as good to excellent by 91% and fair by 9%. The future is regarded as hopeful or promising by 80%. Similarly, 89% are satisfied with life in general; 95% said health never or seldom interferes with family life; 95% feel health and drug side effects are of no or minor concern in sexual relationships. Only 3% feel health is a problem in maintaining a sexual relationship (41% are not sexually active). Only 4% stated that health often interferes with social life; 98% meet with friends on a regular basis; 76% are satisfied with personal relationships and 8% dissatisfied; 91% are satisfied with their ability to perform at work or school and 5% dissatisfied. Of note, 32% are dissatisfied with body appearance. Major concerns are short stature and brittle bones. Major suggestions include education/support groups to deal with teasing at school and peer problems. We conclude that transplanted children with long-term graft function have a favorable social and professional outcome. Overall, quality of life seems excellent.

Adolescent↗
PubMed1990

Alport syndrome, basement membranes and collagen.

Alport syndrome, an inherited disorder of the kidney, eye and ear, has fascinated nephrologists, pathologists, and geneticists for nearly a century. With the recent application of molecular biochemical and genetic techniques, this mysterious disease has begun to yield some of its secrets. Alport syndrome can now be viewed as a generalized disorder of basement membranes that appears to result from mutations in an X-chromosome-encoded basement membrane collagen chain. This chain, along with two other novel collagen chains, is absent from Alport basement membranes, in contrast to the classical chains of collagen IV. Phenotypic heterogeneity in Alport syndrome probably arises from allelic mutations at a single genetic locus. The phenomenon of post-transplant anti-glomerular basement membrane nephritis may be a manifestation of specific mutations at the Alport locus that prevent synthesis of the gene's protein product and the establishment of immunological tolerance.

Basement Membrane↗
PubMed1990

Gene mapping in Alport families with different basement membrane antigenic phenotypes.

The present study was undertaken to determine whether differences among Alport kindreds in the antigenic phenotypes of their basement membranes result from defects at distinct genetic loci or from allelic mutations at a single locus. We analyzed linkage of the Alport gene to polymorphic loci on the X chromosome in three families with Alport syndrome. In two of the families, epidermal basement membranes of affected members showed altered immunohistologic reactivity with a discriminating antibody (FNS1) that identified a 26 kD peptide in the NCl domain of basement membrane collagen. In the third family epidermal basement membranes of affected individuals reacted normally with the antibody. The disease gene mapped to the Xq21-q22 region of the long arm of the X chromosome in the two families with altered basement membrane antigenicity and in the family with normal basement membrane antigens. We conclude that Alport syndrome in each of these kindreds arose from allelic mutations at a single genetic locus, although we cannot at this time exclude the possibility that two or more tightly linked genes are involved. As the genes for the known chains of type IV collagen are on chromosome 13, our findings suggest that the Alport gene may encode a new basement membrane collagen chain.

Antibodies↗
PubMed1990

Posttransplant anti-glomerular basement membrane nephritis in related males with Alport syndrome.

This report describes the development of anti-glomerular basement membrane (GBM) glomerulonephritis after kidney transplantation in related males with Alport syndrome. Antibodies in sera from one of these patients stained normal GBM, Bowman's capsule, tubular basement membranes, and epidermal basement membranes but did not stain tissues from an unrelated Alport male. The target antigen was found to be a 26 kd peptide of the noncollagenous domain of basement membrane collagen. This study provides further evidence of the importance of abnormalities of basement membrane collagen in the pathogenesis of the Alport nephropathy. We speculate that certain mutations at the Alport locus, such as large intragenic deletions or frame-shift mutations, may be associated with failure to develop immune tolerance to epitopes on this 26kd peptide. In the setting of permissive immune response and regulation, transplantation of a normal kidney may result in the generation of anti-GBM antibodies.

Basement Membrane↗
PubMed1990

Dense intramembranous deposit disease: a clinical comparison of histological subtypes.

The accumulation of osmiophilic dense deposits in glomerular mesangial and basement membranes (dense intramembranous deposit disease, or DIDD) is associated with variable histologic alterations of the kidneys. We compared clinical features and long-term renal outcome in 21 patients representing two histologic subtypes of DIDD, namely membranoproliferative glomerulonephritis (MPGN) and focal segmental glomerulonephritis (FSGN). We found that MPGN-type DIDD in 12 patients was associated with nephrotic syndrome in 12, persistent hypocomplementemia in 10 and progression to chronic renal insufficiency in 8. In 9 patients with the focal segmental variety of DIDD, nephrotic syndrome was observed in 3, persistent hypocomplementemia in none, and progression to renal insufficiency in 2 (significance: nephrotic syndrome, p = 0.001; persistent hypocomplementemia, p = 0.0001; chronic renal insufficiency, p = 0.02). In one patient transition from focal segmental to MPGN-type DIDD was observed. We conclude that DIDD is a heterogeneous disorder, and that certain clinical and histologic features may be useful in predicting ultimate outcome.

Adolescent↗
PubMed1989

Proteinuria in a child with sialidosis: case report and histological studies.

A 9-year-old body with sialidosis had nephrotic-range proteinuria. Histological studies demonstrated massive distension of renal cells, particularly glomerular visceral epithelial cells, by cytoplasmic vesicles which contained material reactive with concanavalin A and wheat-germ agglutinin. In addition, some glomeruli exhibited segmental mesangial thickening or glomerulosclerosis. Ultrastructurally, focal detachment of visceral epithelial cells from the underlying glomerular basement membrane was observed. We postulate that glomerular visceral epithelial cell dysfunction may underlie the proteinuria and focal glomerulosclerosis exhibited by this patient. Hyperfiltration, as suggested by the child's elevated creatinine clearances, may be a contributing factor.

Child↗
PubMed1989

Identification of variant Alport phenotypes using an Alport-specific antibody probe.

An antibody, which recognizes an epitope(s) on a 26 kD peptide of the noncollagenous domain of type IV collagen and which fails to bind to basement membranes of individuals with Alport syndrome, was used to characterize members of families representing phenotypic variants of the disorder. Ten of 11 families with juvenile-onset renal failure and 4 of 5 families with adult-onset renal failure exhibited loss of the epitope(s) from epidermal and/or renal basement membranes by indirect immunofluorescence. Two families with typical Alport nephropathy but normal hearing exhibited the same abnormality. This study provides strong evidence that a defect in the main noncollagenous domain of type IV collagen is common to the various phenotypes of Alport syndrome.

Antibodies↗
PubMed1987

Alport familial nephritis. Absence of 28 kilodalton non-collagenous monomers of type IV collagen in glomerular basement membrane.

Alport-type familial nephritis (FN), a genetic disorder, results in progressive renal insufficiency and sensorineural hearing loss. Immunochemical and biochemical analyses of the non-collagenous (NC1) domain of type IV collagen isolated from the glomerular basement membranes (GBM) of three males with this disease demonstrate absence of the normally occurring 28-kilodalton (kD) NC1 monomers, but persistence of the 26- and 24-kD monomeric subunits derived from alpha 1 and 2 (both type IV) collagen chains, respectively.

Basement Membrane↗
PubMed1986

Antihypertensive drug therapy with captopril in children and adolescents.

Captopril was administered to three groups of hypertensive children and adolescents: patients with renal disease; neonates with umbilical artery related hypertension; and post-renal transplant patients. In older children with renal disease, increasing the captopril dose above 0.5 mg/kg did not improve the antihypertensive response. A maximal drug concentrations occurred one hour after dosing, and captopril concentration returned to predose levels by eight hours. Neonates responded to significantly lower doses of captopril (0.01-0.5 mg/kg) and the duration of response to higher doses appeared to be longer than that observed in older children. In post-renal transplant patients, blood pressure decreased after captopril in 94% of subjects, but in 62% a concomitant increase in serum creatinine was observed (correlation [r] = 0.55, p less than .02). This increase could not be correlated with renal biopsy histopathology. Thus, captopril has proven to be an effective antihypertensive agent in children over a broad age range and for a variety of clinical conditions.

Adolescent↗