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Biomedical subjects

E D Avner

Publications and source records attributed to E D Avner.

At least 55 records · Page 3Linked to original sources
PubMed1995

Renal transplantation and chronic dialysis in children and adolescents: the 1993 annual report of the North American Pediatric Renal Transplant Cooperative Study.

The 1993 North American Pediatric Renal Transplant Cooperative Study annual report summarizes data voluntarily contributed by 82 participating centers on 3,223 pediatric patients who received 2,819 renal transplants from January 1987 through January 1993 and 999 independent courses of dialysis from January 1992 through January 1993. In addition to updating information regarding trends and outcomes in pediatric renal transplantation presented in previous annual reports, 1st-year registry data are presented regarding current practices and trends in chronic dialysis therapy for children and adolescents in North America. Living donor graft (LDG) survival rate was 90% at 1 year, 85% at 2 years and 75% at 5 years post transplant. Cadaver graft (CG) survival rates were 76%, 71% and 62% at 1, 2 and 5 years post transplant, respectively. Overall mortality post transplantation continues to be low (CG 6.8%, LDG 4%), mortality remains high in young infants. The dialysis cohort was generally younger than the transplantation cohort. In all age groups, peritoneal dialysis was utilized in the majority of pediatric patients and the overall incidence of peritonitis was 1 episode per 8.2 patients months. External percutaneous catheters were utilized as the predominant chronic hemodialysis access in the study, and access site infections ranged from 6.9% at 1 month to 13.5% at 6 months.

Adolescent↗
PubMed1995

Congenital nephropathies and uropathies.

Although congenital nephropathies and uropathies only represent a fraction of possible genitourinary diseases detected during childhood, they have serious and sometimes avoidable morbidity and mortality. Advances in genetic, molecular, and cellular biology research continue to better define embryologic insults to normal organogenesis and offer the promise that many of these conditions might be avoided in the future. For now, awareness of these entities and their varied presentations and manifestations is crucial so that prompt evaluation and aggressive multidisciplinary management assures the affected child optimal growth and development.

Humans↗
PubMed1995

Tyrosine kinase activity of the EGF receptor in murine metanephric organ culture.

Epidermal growth factor (EGF) and its fetal form, transforming growth factor alpha (TGF-alpha) are renal mitogens which induce epithelial hyperplasia, proximal tubular cyst formation (TC), and accelerated distal nephron differentiation in metanephric organ culture. To delineate the intracellular mechanisms mediating these growth factor effects, we studied the specific role of the epidermal growth factor receptor (EGF-R), the common receptor for both ligands, as an activated tyrosine kinase in TC formation and nephrogenesis. Fetal murine metanephric explants were incubated for 120 hours in control, and EGF (15 ng/ml)/TGF-alpha (10 ng/ml) supplemented medium with and without EGF-R blocking monoclonal antibody (50 mg/ml), or tyrosine kinase inhibitor. EGF-R tyrosine kinase inhibition was achieved by incubation with a synthetic tyrphostin (TP B42) (0.1 microM) or genestein (5.5 micrograms/ml). The following parameters were assessed: (a) segment-specific nephron development using morphometry and immunohistology; (b) tubular epithelial hyperplasia by protein content and BrdU uptake; and (c) TC formation by morphometric cystic index. Both growth factors produced hyperplastic proximal TC, significantly increased explant growth, and significantly increased distal nephron differentiation. Inhibiting the ligand-EGF-R interaction with EGF-R blocking monoclonal antibody abolished all growth factor-induced effects and resulted in increased amounts of undifferentiated mesenchyme and decreased distal nephron differentiation. Inhibition of EGF-R tyrosine kinase activity with either Tyrphostin B42 or genestein blocked TC formation and produced nodular blastemal hyperplasia and decreased distal nephron differentiation.

Animals↗
PubMed1995

Epidermal growth factor receptor expression is abnormal in murine polycystic kidney.

Renal tubular cyst formation and progressive enlargement in autosomal recessive polycystic kidney disease (ARPKD) are mediated by increased epithelial cell proliferation and altered transtubular fluid transport. Epidermal growth factor (EGF)-like peptides have been proposed to play roles in normal nephrogenesis and cystic tubular mitogenesis. Therefore, renal expression of EGF receptor (EGFR) protein and mRNA was examined in an animal model for ARPKD, the C57BL/6Jcpk/cpk (CPK) mouse. Both quantitative and qualitative abnormalities of EGFR expression were demonstrated. While both control and cystic proximal tubules, as well as control collecting tubules, demonstrated exclusive basalateral EGFR protein expression, cystic collecting tubules exhibited significant apical-lateral receptor localization. During nephrogenesis, EGFR protein expression was elevated in CPK renal tissue when compared to developmentally staged controls. Control and CPK kidneys expressed the same species of EGFR mRNA. Levels increased with developmental age, but were significantly higher at each stage of development in CPK kidneys. Overexpression of both EGFR protein and mRNA in CPK mice suggests altered control of EGFR protein and/or gene expression. EGFR mislocalization and overexpression may be mechanisms whereby the EGF-like factors in cyst fluid stimulate cystogenesis through an autocrine-paracrine cycle in ARPKD.

Animals↗
PubMed1995

1 alpha, 25-dihydroxyvitamin D3 receptor ontogenesis in fetal renal development.

We used immunohistochemical techniques to examine the distribution of 1 alpha, 25-dihydroxyvitamin D3 receptors (VDR) in developing rat and mouse kidneys and murine metanephric organ culture. In vivo, the patterns of expression in the two species were similar despite the slight difference in gestational periods (rat, 22 days; mouse, 19 days). Starting at gestational day 15, epitopes for VDR were found in cells of branching ureteral buds and in surrounding mesenchyme and at later developmental stages in glomerular visceral and parietal epithelial cells and proximal and distal tubules (DT). Epitopes for the 28-kDa calcium-binding protein (calbindin D28k) were found exclusively in DTs starting at gestational day 19. The pattern of VDR expression during in vitro nephrogenesis in serum-free murine metanephric organ culture paralleled that seen in vivo. At the time of explantation into organ culture (gestational day 13), VDR epitopes were not detected. By 3 days of in vitro development, VDR expression was identical to that found in gestational day 15 metanephroi in vivo. VDR expression after 5 days of in vitro development mirrored the pattern of gestational day 17 metanephroi in vivo. No calbindin D28k epitopes were seen at any in vitro developmental stage studied. We demonstrate for the first time that VDR are present in specific areas of the developing rat and mouse kidney early in gestation. Calbindin D28k appears later in developing rat and mouse kidney and is distributed differently than the VDR. Metanephric organ culture may be a useful model for studying the regulation and function of VDR during early renal development.

Animals↗
PubMed1995

Biliary epithelial cells from mice with congenital polycystic kidney disease are hyperresponsive to epidermal growth factor.

Epithelial hyperplasia is an early feature of the renal and biliary lesions in autosomal recessive polycystic kidney disease (ARPKD). To explore the cellular basis of this hyperplasia we isolated, cultured, and characterized biliary tract epithelium from common bile duct explants of mice with ARPKD (the BPK mouse) and controls. Primary cultures resulted in dense colonies of contact-inhibited epithelial cells with a homogenous growth pattern. Colony growth in serum-free basal medium (BM) of BPK-derived cells was not different from controls. Supplementation of BM with epidermal growth factor (EGF) induced a proliferative response in BPK-derived cells that was significantly increased over controls as assessed by [3H]thymidine uptake and expressed as percent change over growth in BM (BPK 239% and controls 131% of BM growth). In contrast, no differences between BPK- and control-derived cells were found with regard to the effects of BM supplementation with IGF-I, IGF-II, acidic fibroblast growth factor, keratinocyte growth factor, hepatocyte growth factor, or transforming growth factor-beta. Primary culture of biliary epithelium may provide a useful in vitro model for the study of the cellular pathophysiology of ARPKD. Our data demonstrate that increased epithelial sensitivity to EGF-like proteins may play a role in biliary epithelial proliferative changes which parallel renal tubular epithelial proliferation in ARPKD.

Animals↗
PubMed1995

Metabolic studies of rat renal tubule cells loaded with cystine: the cystine dimethylester model of cystinosis.

The cause of Fanconi syndrome in cystinosis is enigmatic. It has previously been shown that renal tubules could be loaded with cystine by incubating them with cystine dimethylester (CDE), mimicking the biochemical hallmark of cystinosis. Such tubules have impaired transport, decreased whole-cell O2 consumption, and substrate utilization. In this study, the metabolic disturbances in cystine-loaded renal tubule cells were further characterized. Isolated rat renal tubules were loaded with cystine by incubating them with 2 mM CDE for 10 min. This had no significant effect on total ATPase, Na(+)-K(+)-ATPase, or the ouabain-insensitive ATPase activity of renal tissue homogenates from these cystine-loaded tubules. Intracellular K was significantly lower in the cystine-loaded tubules (37 +/- 2 versus 47 +/- 3 nEq/mg; P < 0.008). Intracellular ATP was reduced by 39% in the cystine-loaded tubules (23.7 +/- 2.4 versus 38.1 +/- 3.3 nmol/mg of protein; P < 0.0025). CDE (2 mM) reduced isolated mitochondrial O2 consumption with glutamate as the substrate by 66% (4.7 +/- 0.7 versus 13.9 +/- 0.8 nm/min per mg of protein, P < 0.001) but had no effect on mitochondrial O2 consumption with succinate as the substrate. It was speculated that the impaired transport from cystine loading with CDE is secondary to a decrease in energy generation.

Adenosine Triphosphate↗
PubMed1995

Cystic maldevelopment of the kidney.

Cystic maldevelopment of the kidney can occur when the normal processes of nephrogenesis are disrupted. The result is formation and enlargement of fluid-filled cysts instead of normal renal tubules. Several human disease states are associated with the development of renal cysts. Events triggered by genetic mutation or environmental insult probably lead to the combination of factors believed to stimulate cyst formation and enlargement, including epithelial hyperplasia, abnormal protein sorting, altered fluid transport, and abnormal extracellular matrix:cell interactions. A precise delineation of the cellular pathophysiology of renal cystic maldevelopment has the potential to do the following: (1) focus genetic investigation on specific "cystic" candidate genes; (2) provide models for the definitive identification of such candidate genes; and (3) provide key targets for immunotherapy or pharmacotherapy designed to prevent renal cyst formation and progressive enlargement.

Animals↗
PubMed1995

The severe perinatal form of autosomal recessive polycystic kidney disease maps to chromosome 6p21.1-p12: implications for genetic counseling.

Autosomal recessive polycystic kidney disease (ARPKD) is a one of the most common hereditary renal cystic diseases in children. Its clinical spectrum is widely variable with most cases presenting in infancy. Most affected neonates die within the first few hours of life. At present, prenatal diagnosis relies on fetal sonography, which is often imprecise in detecting even the severe form of the disease. Recently, in a cohort of families with mostly milder ARPKD phenotypes, an ARPKD locus was mapped to a 13-cM region of chromosome 6p21-cen. To determine whether severe perinatal ARPKD also maps to chromosome 6p, we have analyzed the segregation of seven microsatellite markers from the ARPKD interval in 22 families with the severe phenotype. In the majority of the affected infants, ARPKD was documented by histopathology. Our data confirm linkage and refine the ARPKD region to a 3.8-cM interval, delimited by the markers D6S465/D6S427/D6S436/D6S272 and D6S466. Taken together, these results suggest that, despite the wide variability in clinical phenotypes, there is a single ARPKD gene. These linkage data and the absence of genetic heterogeneity in all families tested to date have important implications for DNA-based prenatal diagnoses as well as for the isolation of the ARPKD gene.

Amniocentesis↗
PubMed1995

Hypercalciuria and nephrocalcinosis in the oculocerebrorenal syndrome.

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.

Calcium↗
PubMed1994

Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice.

A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.

Amino Acid Sequence↗
PubMed1994

Escherichia coli O 157:H7-associated hemolytic-uremic syndrome after ingestion of contaminated hamburgers.

We conducted a retrospective analysis of 37 children with Escherichia coli O157:H7-associated hemolytic-uremic syndrome. The infection was traced to contaminated hamburgers at a fast-food restaurant chain. Within 5 days of the first confirmed case, the Washington State Department of Health identified the source and interrupted transmission of infection. Ninety-five percent of the children initially had severe hemorrhagic colitis. Nineteen patients (51%) had significant extrarenal abnormalities, including pancreatitis, colonic necrosis, glucose intolerance, coma, stroke, seizures, myocardial dysfunction, pericardial effusions, adult respiratory disease syndrome, and pleural effusions. Three deaths occurred, each in children with severe multisystem disease. At follow-up two children have significant impairment of renal function (glomerular filtration rate < 80 ml/min/per 1.73 Hm2); both of these children have a normal serum creatinine concentration. Hemolytic-uremic syndrome is the most common cause of acute renal failure in children, and this experience emphasizes the systemic nature of this disease. Clinicians should anticipate that multisystem involvement may occur in these patients, necessitating acute intervention or chronic follow-up. This outbreak of Hemolytic-uremic syndrome also highlights the microbiologic hazards of inadequately prepared food and emphasizes the importance of public health intervention in controlling Hemolytic-uremic syndrome.

Adolescent↗
PubMed1993

Renal and biliary abnormalities in a new murine model of autosomal recessive polycystic kidney disease.

Current models of autosomal recessive polycystic kidney disease (ARPKD) fail to demonstrate biliary abnormalities in association with renal cysts. We therefore studied a new murine model of ARPKD in which dual renal tubular and biliary epithelial abnormalities are present. Affected homozygous animals typically die 1 month postnatally in renal failure with progressively enlarged kidneys. Renal cysts shift in site from inner cortical proximal tubules at birth to collecting tubules 20 days later, as determined by segment-specific lectin binding. Increased numbers of mitosis were demonstrated in proximal and collecting tubular cysts. In addition, epithelial hyperplasia was demonstrated morphometrically in the intra- and extrahepatic biliary tract of affected animals. The number of intrahepatic biliary epithelial cells was increased by 50% on postnatal day 5 and by 100% on postnatal day 25 (P < 0.01). Despite an increased frequency of "chaotic" portal areas in mice with renal cysts, no intrahepatic cysts or shape abnormalities of the biliary lumen were detected using biliary casts and morphometry. Additionally there was nonobstructive hyperplastic dilatation of the extrahepatic biliary tract which was linked in all animals to the presence of renal cysts. The hyperplastic abnormalities in both renal and biliary epithelium make this new mouse strain a good model for the study of the dual organ cellular pathophysiology of ARPKD.

Animals↗
PubMed1993

Normal and abnormal nephrogenesis.

During the past decade, exciting advances in the fields of cell and molecular biology have provided new insight into the processes of normal and abnormal nephron induction and renal morphogenesis. Although the specific molecular signals that control renal mesenchymal-epithelium inductive interaction remain unknown, recent data suggest that postinductive nephrogenesis may be regulated by the overall balance of a number of local autocrine and/or paracrine growth factor systems. Alterations in the critical balance of regulatory factors might produce a variety of hypoplastic and dysplastic nephropathies or hyperplastic lesions such as tubular cysts. Additional studies demonstrate that extracellular matrix components and cell surface integrins have important regulatory roles in ureteric bud development and branching. Perturbations in matrix or integrin expression due to altered gene activity or toxin exposure would be expected to produce a variety of renal abnormalities ranging from failure of nephron induction (aplasia) to focal disruptions of differentiation (segmental dysplasia). Finally, several groups of genes encoding transcriptional regulatory proteins have been identified that appear to regulate aspects of cell proliferation, pattern formation, and segment-specific differentiation during normal and abnormal nephrogenesis. Future studies will elucidate the roles that specific genes and proteins play in renal development and will ultimately reveal the manner in which their dysregulation or dysfunction causes a variety of developmental renal disorders.

Animals↗