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Biomedical subjects

E D Avner

Publications and source records attributed to E D Avner.

At least 91 records · Page 5Linked to original sources
PubMed1987

Congenital murine polycystic kidney disease. I. The ontogeny of tubular cyst formation.

In the current study, the ontogeny of tubular cyst formation was studied in the CPK mouse, a murine strain with autosomal recessive polycystic kidney disease. Utilizing the technique of intact nephron microdissection in addition to standard light and transmission electron microscopy, the earliest morphologic alterations in CPK kidneys were localized in fetal tissue at 17 days of gestation to the distal portion of developing proximal tubules. During disease progression, from birth to 21 days of postnatal age, there was a shift in the site of cystic nephron involvement from proximal tubule to collecting tubules without involvement of other nephron segments. Cysts were enlarged tubular segments which remained in continuity with other portions of the nephron and were not associated with abnormalities in the overall pattern of nephron growth or differentiation. Analysis suggested that alterations in transtubular transport in abnormally shortened proximal tubular segments of juxtamedullary nephrons may have pathogenic importance in the early stages of cyst formation, and that epithelial hyperplasia and cytoskeletal alterations may have a role in progressive proximal tubular cystic enlargement. Cellular hyperplasia of epithelial walls of normally formed tubules was a prominent feature of cyst formation and progressive enlargement in collecting tubules. Such data form the basis for future studies into specific pathophysiological processes which may be operative in specific nephron segments during different stages of cyst formation in the CPK mouse.

Animals↗
PubMed1987

Silica and glomerulonephritis: case report and review of the literature.

A 54-year-old foundry worker with extensive silica exposure, but no pulmonary disease, developed the nephrotic syndrome and renal failure over a 3-month period. Renal biopsy demonstrated a proliferative glomerulonephritis; energy dispersive x-ray analysis detected silicon within the renal tubules. Measurements of respirable silica at the foundry revealed levels up to 2.5 times the current occupational standard. Similar glomerular disease has been reported in silica-exposed animals and workers with silicosis. This case suggests that clinicians should include silica exposure in the differential diagnosis of unexplained diffuse proliferative glomerulonephritis, renal disease may occur without clinically evident pulmonary disease in silica exposure, and silica-induced glomerulonephritis warrants further clinical and epidemiologic research.

Glomerulonephritis↗
PubMed1987

Glucocorticoids modulate renal glucocorticoid receptors and Na-K ATPase activity.

Primary cultures of mouse renal tubular epithelial cells were used to study the effect of hydrocortisone on the regulation of glucocorticoid receptors (GR) and on sodium-potassium adenosine triphosphatase (Na-K ATPase) activity. A GR assay was developed and performed directly on cell monolayers maintained in serum-free medium to which hydrocortisone at 5 nM, 50 nM, and 5 X 10(-4) M was added. Compared with control cells grown in medium without hydrocortisone, GR levels per cell decreased by 50% after 48 hours of growth in medium containing 5 nM hydrocortisone concentrations (50 nM or 5 X 10(-4) M), GR levels decreased to less than or equal to 28% of control values. In all hydrocortisone treatment groups there was an inverse relation between GR concentrations and Na-K ATPase activity. Binding of cell GR by the addition of the antiglucocorticoid RU 38486 in hydrocortisone-supplemented medium eliminated the glucocorticoid-induced stimulation of Na-K ATPase activity. These results demonstrate a time- and dose-dependent effect of glucocorticoids on GR binding activity and a direct relation between this receptor-hormone interaction and Na-K ATPase activity in intact renal tubular epithelial cells.

Animals↗
PubMed1987

Reversible inhibition of cytosolic glucocorticoid receptors by mercurial agents. Application in the measurement of total and unoccupied receptors.

Recently developed "exchange assays" have been used to measure total cytosolic glucocorticoid receptor (GR) binding activity as compared to standard GR assays which measure unoccupied receptor. In the current study we modified these methods and extended the applications of such assays. Experiments defined the conditions whereby two sulfhydryl-binding agents, p-hydroxymercuribenzoate (PHMB) and mersalyl, completely inhibited binding of the glucocorticoid receptor to ligand in mouse renal cytosol. Reactivation of steroid-binding activity was restored by addition of dithiothreitol. The present study demonstrates 12% higher GR binding activity when this exchange assay is performed using saturated glucocorticoid-receptor complex, rather than standard cytosol. Combining the data from the standard and exchange mouse renal cytosolic GR assays, it was determined that, at physiologic tissue corticosterone levels, the respective mean concentrations of unoccupied, occupied, and total GR were 467, 89, and 556 fmol/mg cytosol protein. Measurement of receptor concentrations by the use of these methods permits precise experimental differentiation of factors which affect total, as well as unoccupied GR.

Animals↗
PubMed1987

Triiodothyronine-induced cyst formation in metanephric organ culture: the role of increased Na-K-adenosine triphosphatase activity.

Previous organ culture investigations into the pathogenesis of renal cyst formation have demonstrated that glucocorticoid-induced proximal tubular cyst formation is associated with increases in renal sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity. To explore the relationship between cyst production and transport enzyme induction, we examined the effects of the potent inducer of Na-K-ATPase activity, L-3,5,3'-triiodothyronine (T3), on renal tubular morphologic and enzymatic development in murine metanephric organ culture. The addition of T3 (2 X 10(-8) mol/L) to completely characterized, serum-free growth medium produced striking proximal tubular cystic abnormalities. Frank cyst development was preceded by ultrastructural alterations consisting of basolateral intercellular spreading, which increased with progressive tubular dilation. Ultrastructural analysis demonstrated no abnormalities of tubular cyst wall basal laminae, and immunohistologic staining with affinity-purified antibodies to the basal lamina glycoproteins fibronectin, laminin, and entactin, revealed no differences between cystic and control tissue. With use of an enzyme-linked kinetic microassay, T3-induced cystic organ culture explants (CY) showed significant increases in Na-K-ATPase when compared with controls from 72 to 120 hours of organ culture incubation. The initial differences in CY Na-K-ATPase occurred contemporaneously with the earliest ultrastructural evidence of cyst formation, and subsequent increases paralleled progressive tubular cyst formation. Tubular cyst formation in CY could be largely prevented by daily incubation of explants with ouabain, 0.2 mmol/L (final concentration) for 120 minutes without deleterious effects on overall metanephric development. We conclude that T3 induces proximal tubular cyst formation in metanephric organ culture, and that T3-induced increases in Na-K-ATPase have a primary role in the pathogenesis of tubular cyst formation in this model system.

Animals↗
PubMed1986

Partial characterization and ontogeny of renal cytosolic glucocorticoid receptors in mouse kidney.

The glucocorticoid receptor (GR) was partially characterized in mouse renal cytosol. A sensitive and reproducible [3H]dexamethasone binding assay suitable for use with small quantities of cytosolic protein, was developed. Studies defined the optimal equilibrium binding conditions, metabolism of [3H]dexamethasone in adult renal cytosol, specificity of binding of the GR, and molecular weight of the GR-[3H]dexamethasone complex by gel filtration chromatography. The assay was subsequently used to measure the renal GR during different stages of foetal and postnatal development, as well as in glomerular and renal tubular preparations from adult mice. An almost linear increase in GR occurred from day 13 to day 18 of gestation with levels rising from 100 to 201 fmol/mg cytosol protein; this was followed by a sharp rise in receptor concentration just after birth to 343 fmol/mg cytosol protein. Adult levels, 410-433 fmol/mg cytosol protein, were reached by 2 weeks after birth. The equilibrium dissociation constants (Kd) of the [3H]dexamethasone-receptor complex were similar in adult and in embryonic cytosols (range, 2.8-11.8 nM; mean +/- SD = 6.5 +/- 2.9 nM). Specific binding was assessed to be 3- to 5-fold greater in tubular than in glomerular preparations. These data on the localization and ontogeny of GR during murine metanephric development provide a basis for study of glucocorticoid-mediated effects on various models of congenital and acquired renal disease.

Aldosterone↗
PubMed1986

Renal failure in children with hepatic failure undergoing liver transplantation.

Over a 3 1/2 year period, 133 children with hepatic failure underwent orthotopic liver transplantation (OLT) at our center. Renal failure (creatinine clearance less than 20 ml/min/1.73 m2) was present in 19 (14.3%) of these children. In seven of the 19 children, renal failure was present before OLT, and in the other 12 after OLT. The causes of renal failure included hepatorenal syndrome in seven, postischemic acute tubular necrosis in five, severe prerenal azotemia in five, and cyclosporine nephrotoxicity in two. Eight other patients died of renal failure while awaiting emergency transplantation. Of the total of 31 deaths among 133 children who underwent OLT, nine occurred in the 19 patients with renal failure. Thus patients with OLT and renal failure had a significantly higher mortality than other patients with transplants (P less than 0.025). Dialysis was not associated with improved survival. The majority of deaths in patients with renal failure were related to severe hemorrhage, thromboembolic events, and systemic fungal infections. Our experience suggests that renal failure is common in children with hepatic failure and is associated with reduced patient survival after OLT.

Acute Kidney Injury↗
PubMed1986

Renal failure and dialysis therapy in children with hepatic failure in the perioperative period of orthotopic liver transplantation.

Severe renal failure (GFR less than or equal to 20 ml/min/1.73 m2) complicated the clinical course in 27 of 146 children (18.5%) admitted for orthotopic liver transplantation (OLT). Hepatorenal syndrome (HRS) was the cause of renal failure in 12 of 15 patients in whom renal failure preceded OLT while acute tubular necrosis, pre-renal factors and cyclosporine nephrotoxicity were the major causes of renal failure post-OLT. Eight patients died from hemorrhage, infection or other complications of hepatic failure before OLT could be performed. Survival in the remaining 19 patients undergoing OLT was significantly lower compared to 114 patients with OLT and no renal failure (53% vs 81%, p less than 0.025). Dialysis therapy in 13 of the 27 patients with renal failure (10 hemodialysis and 3 peritoneal dialysis) was frequently complicated by severe gastrointestinal hemorrhage and hypotension, and directly contributed to the death of two patients prior to OLT. Among the 19 patients with renal failure who were actually transplanted, the survival rate was similar whether dialysis was used or not (5/10 vs 5/9) even though the mean GFR was significantly lower in dialyzed patients (p less than 0.05). However, although small patient numbers precluded meaningful statistical analysis, dialysis appeared to be beneficial for the subgroup of 12 patients with HRS, 4 of whom had complete recovery of renal function after successful OLT. We conclude that, renal failure is common in children with advanced liver failure; dialysis in such patients may increase morbidity and does not improve overall mortality; and dialysis support may improve survival in the subgroup of patients with HRS.

Acute Kidney Injury↗
PubMed1985

Renal function and somatic growth in pediatric cadaveric renal transplantation with cyclosporine-prednisone immunosuppression.

The posttransplantation courses of 28 consecutive patients (age range, 0.8 to 16 years) who received cadaveric renal allografts and combined cyclosporine-low-dose prednisone immunosuppression were analyzed. The mean follow-up time was 16.5 months (range, four to 42 months). There was one death and the actuarial one-year graft survival was 59%. At follow-up, the group mean (+/- SD) serum creatinine concentration in 14 patients with functioning grafts was nearly double the expected mean value for normal children of similar age and sex (1.13 +/- 0.38 vs 0.61 +/- 0.07 mg/dL), and the mean +/- SD glomerular filtration rate was 76.5 +/- 20.0 mL/min/1.73 sq m (range, 40 to 115.5 mL/min/1.73 sq m). Although rejection accounted for 11 (79%) of 14 graft losses, failure of immunosuppression could be implicated in only four of these patients. Among eight preadolescent patients with good renal function for one year posttransplantation, somatic growth was poor in four and suboptimal in three patients; catch-up growth occurred in one patient. In such patients, the weight-for-height index increased, reflecting the development of obesity after transplantation. We conclude that cyclosporin-low-dose prednisone offers little or no advantage in terms of cadaveric renal allograft survival or stimulation of somatic growth when compared with conventional therapy.

Adolescent↗
PubMed1985

Growth factor requirements of organogenesis in serum-free metanephric organ culture.

In order to define humoral growth factors which may regulate mammalian renal development, the growth requirements of fetal metanephric organogenesis were studied in serum-free murine organ culture. Metanephric growth, determined by cell proliferation and protein content, and metanephric differentiation, determined morphometrically as epithelial glomerular formation, were compared and contrasted following 144 hours of organ culture incubation in basal medium, basal medium supplemented with 10% fetal bovine serum, and basal medium supplemented with various combinations of growth factors. The basal medium was composed of equal volumes of Dulbecco's modified Eagle's medium and Ham's F-12 medium. Five humoral growth factors were studied in the following concentrations: selenium, 6.8 X 10(-9) M; insulin, 8.3 X 10(-7) M; triiodothyronine, 2 X 10(-9) M; transferrin, 6.2 X 10(-8) M; and prostaglandin E1, 7.1 X 10(-8) M. Results showed that transferrin and prostaglandin E1 were necessary for optimal growth in the system and that prostaglandin E1 was necessary for maximal metanephric differentiation. Such data provide guidelines for the creation of serum-free medium for future fetal renal cell and tissue culture systems, and provide insight into the factors which may regulate normal and abnormal renal embryogenesis and the reparative processes of renal hyperplasia and hypertrophy which follow renal injury.

Alprostadil↗
PubMed1985

Sodium-potassium ATPase activity mediates cyst formation in metanephric organ culture.

To study the possible role of altered transtubular transport in renal tubular cyst formation, the ontogeny of renal Na-K ATPase was studied during glucocorticoid-induced cystic metanephric tubular development in serum-free, murine organ culture (SFMOC). Utilizing an enzyme-linked kinetic microassay, a developmental profile of total ATPase and specific Na-K ATPase activity was established for control (CON) and glucocorticoid-induced cystic organ culture (CY) explants. During 120 hr of CON and CY organ culture nephrogenesis total Na-K ATPase activity, specific Na-K ATPase activity, and the Na-K ATPase: total ATPase ratio progressively increased, simulating normal in vivo murine enzyme development. However, from 48 to 120 hr of organ culture, CY showed significant increases in Na-K ATPase activity when compared to CON at similar stages of development. Na-K ATPase activity (expressed as nmoles . min-1 . mg protein -1, mean +/- SD) was, at: 48 hr, CY 13.1 +/- 0.7 vs. CON 11.0 +/- 0.9 (P less than 0.01); 72 hr, CY 16.4 +/- 1.1 vs. CON 12.2 +/- 0.7 (P less than 0.001); 96 hr, CY 35.4 +/- 4.9 vs. CON 13.7 +/- 0.4 (P less than 0.001); and 120 hr, CY 26.1 +/- 1.4 vs. CON 16.3 +/- 0.9 (P less than 0.001). The initial differences in CY enzyme activity preceded the earliest ultrastructural evidence of cyst formation by 18 to 24 hr, while subsequent increases in Na-K ATPase activity in CY paralleled progressive tubular cyst formation. Tubular cyst formation in CY could be largely prevented by daily incubation of explants with ouabain, 0.2 mM (final concentration) X 120 min, without deleterious effects on overall metanephric development.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

A new model of glucocorticoid-induced metanephric maldevelopment.

A new experimental model of glucocorticoid-induced tubular cyst formation has been developed in metanephric organ culture. The addition of cortisol (1.4 X 10(-5) M) to chemically defined serum-free culture medium produces cystic changes during in vitro nephrogenesis . The model isolates the role of glucocorticoids in experimental cyst formation.

Animals↗
PubMed1984

Hydrocortisone-induced cystic metanephric maldevelopment in serum-free organ culture.

To investigate the basic pathophysiology of renal cystic maldevelopment, the production of renal cysts was studied in a newly developed murine metanephric organ culture system. In this isolated, nonvascularized system, the addition of hydrocortisone (1.4 X 10(-5) M) to completely characterized, serum-free growth medium produced striking tubular cystic abnormalities. As nephron obstruction did not occur in the nonperfused organ culture system in which neither glomerular filtration nor urine flow were present, the model experimentally isolated the roles of tubular cell metabolism and tubular wall extracellular matrix development in the production of cystic alterations. Analysis with the techniques of intact nephron microdissection and light and electron microscopy demonstrated that organ culture cysts developed in proximal tubules amid a normal background of organotypic tubular differentiation and glomerular epithelial development. Frank cystic development in the system was regularly preceded by ultrastructural alterations in and around the walls of differentiating proximal tubules. Such changes consisted of basolateral intercellular spreading which increased with progressive tubular dilation and irregular thickening and lamellation of tubular basal laminae. The ultrastructural features of the model suggest roles for hydrocortisone-induced alterations in both tubular transport processes and basal lamina structure in the experimental production of cysts. We conclude that the production of cystic changes in organ culture by hydrocortisone permits highly controlled study of the roles of altered tubular cell and basal lamina metabolism in the pathogenesis of cystic metanephric maldevelopment.

Animals↗
PubMed1983

Cyst formation in metanephric organ culture induced by cis-dichlorodiammineplatinum (II).

A new experimental model of renal tubular cyst formation has been developed in metanephric organ culture. The addition of cis-dichlorodiammineplatinum (II), 50 micrograms/ml, to culture medium induces cystic changes during in vitro nephrogenesis. The model has particular utility in the study of basic mechanisms underlying renal tubular cystic changes, as well as the mechanisms by which nephrotoxins may mediate renal tubular injury.

Animals↗
PubMed1983

Single-dose amoxicillin therapy of uncomplicated pediatric urinary tract infections.

Forty-nine ambulatory children between 2-1/2 and 12 years of age with acute, clinically uncomplicated urinary tract infections caused by susceptible organisms were randomized to receive a single dose of amoxicillin based on weight or a 10-day course of amoxicillin therapy (conventional therapy). Patients receiving single doses of amoxicillin had a cure rate of 63%, which compares unfavorably with the cure rate of 92% in patients given conventional therapy. A failure of single-dose therapy predicted underlying radiologic abnormalities with a sensitivity of 60% and a specificity of 58%, making it a poor screening test for detecting those patients at risk for renal parenchymal damage. The antibody-coated bacteria assay had no predictive value in separating upper and lower tract disease, although it may predict underlying radiologic abnormalities. The data indicate that the response to single-dose amoxicillin therapy fails to separate upper from lower tract disease reliably and has a limited role in predicting response to conventional antimicrobial therapy.

Acute Disease↗
PubMed1983

An organ culture model for the study of metanephric development.

A murine whole organ metanephric culture system was designed to study the developmental aspects of mammalian nephrogenesis. Metanephros and ureteric bud were removed from CFI albino mouse embryos at 13.5 +/- 0.4 days gestation, and grown in Dulbecco's modified Eagle's Minimal Essential Medium supplemented with 20 per cent donor bovine serum at 37C in a mixed air--5 per cent CO2 environment. Under the experimental conditions employed, the metanephric explants showed organotypic tubular and glomerular epithelial development. A well-developed proximal tubule with microvilli, and characteristic intracellular organelles and intercellular junctions developed by 72 hours of culture. By 120 hours of culture, unique devascularized glomeruli consisting of parietal and visceral epithelial layers formed. The glomerular visceral epithelial cells formed foot processes and slit pore diaphragms, and produced islands of basement membrane. No endothelial or mesangial elements were present at any stage in organ culture development, indicating that advanced nephrogenesis can occur following initial epithelial-mesenchymal induction despite the absence of vascularization. The whole organ culture model system isolates renal structural development from the influences of perfusion and urine formation. The system thus affords the opportunity to study normal, as well as abnormal mammalian renal development under highly controlled experimental conditions.

Animals↗