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J D Mahan

Publications and source records attributed to J D Mahan.

36 records · Page 2Linked to original sources
PubMed1990

Experimental glomerulonephritis induced by antigen that binds to glomerular fibronectin.

In previous studies we demonstrated that antigens with the capacity to bind to the glycoprotein fibronectin (FN), localized in the glomerular mesangium after intravenous (IV) injection. In the present study we sought to determine if the localization of FN-binding antigens in the mesangium is capable of inducing glomerulonephritis. A group of rats were injected IV with the FN-binding antigen phenylated gelatin (DNP-GL) followed 2 hours later by rabbit anti-DNP antibodies. This experimental protocol resulted in the development of a glomerulonephritis characterized by an initial heterologous phase and a late autologous phase. Both phases of the disease were characterized by significant histologic changes, including focal segmental mesangial matrix expansion, inflammatory cell infiltration, and an increase in endothelial and mesangial cells. By immunoperoxidase we demonstrated mesangial deposition of rabbit IgG and rat C3 during the initial heterologous phase and mesangial deposition of rat IgG and C3 during the autologous phase. Significant proteinuria developed during the heterologous phase, but not during the autologous phase of the disease. By contrast, rats injected with DNP-GL alone or anti-DNP antibodies alone did not develop significant histologic glomerular changes or proteinuria. In conclusion, antigens that bind to mesangial FN are capable of inducing glomerulonephritis. This mechanism of localization of antigens in the glomeruli may be relevant to human immune complex (IC)-mediated diseases involving antigens that have the capacity to bind to FN.

Animals↗
PubMed1990

Role of precipitating and nonprecipitating antibodies in glomerular immune complex formation.

The present study compared directly the ability of precipitating and nonprecipitating antibodies to form and sustain glomerular immune deposits. The antigen phenylated gelatin (DNP-GL) was injected i.v. into rats. DNP-GL is cleared from the circulation rapidly and becomes localized in glomeruli. Two hours later, rats received either precipitating or nonprecipitating mouse monoclonal anti-DNP antibodies. These antibodies were comparable with respect to size, affinity, number of antigen combining sites and isoelectric point. However, in vitro, nonprecipitating antibodies demonstrated a faster dissociation rate from antigen than precipitating antibodies. Control rats received DNP-GL alone or antibody alone. Antibody deposition in glomeruli was quantitated by Computerized Image Analysis (CIA) of immunoperoxidase stained tissue sections and by glomerular radioactive counts in experiments using 125I labelled antibodies. We demonstrated that glomerular uptake of anti-DNP antibody was similar two hours after injection of precipitating and nonprecipitating antibodies. However, six or more hours after injection, significantly less antibody was present in the glomeruli of rats injected with nonprecipitating antibodies. These differences could not be explained by a greater rate of antigen removal from kidney in rats injected with nonprecipitating antibodies. To assess whether nonprecipitating antibodies modify the glomerular binding and retention of precipitating antibody, in a separate series of experiments rats were injected with equal amounts of precipitating and nonprecipitating antibodies. Both types of antibody bound to glomeruli. However, with time glomerular antibody levels paralleled those found in rats injected with nonprecipitating antibody alone. We conclude that the precipitating characteristics of antibodies do not affect their ability to deposit in kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Urinary calcium excretion in healthy adolescents.

To establish normative data for urinary calcium excretion in healthy adolescents, we measured calcium-creatinine ratios (UCa/Cr) in urine samples collected from 222 middle school teenagers of diverse racial and socioeconomic backgrounds. Median UCa/Cr were: white girls, 0.23 mmol/L per mmol/L (0.08 as mg/dl per mg/dl); black girls, 0.14 (0.05); white boys, 0.14 (0.05); and black boys, 0.08 (0.03). The 95th percentile values for UCa/Cr were: white girls, 0.54 (0.19); black girls, 0.59 (0.21); white boys, 0.68 (0.24); and black boys, 0.50 (0.18). By nonparametric analysis, girls had significantly higher UCa/Cr than boys (p less than 0.01), and whites had significantly higher urinary UCa/Cr than blacks (p less than 0.01). No significant correlation was found between Tanner stage and UCa/Cr in either sex. This study provides data for detecting adolescents with high urine calcium excretion, which should be useful clinically and in studies designed to evaluate the significance of persistent hypercalciuria.

Adolescent↗
PubMed1989

Localization of decay accelerating factor in normal and diseased kidneys.

Decay accelerating factor (DAF) is a cell membrane associated glycoprotein that inhibits C3 activation. In the present study we evaluated the presence of DAF in normal (N = 15) and diseased human kidneys (N = 76). Sections of frozen tissue were stained for DAF by immunoperoxidase, utilizing three mouse monoclonal anti-DAF anti-bodies. In normal kidneys, DAF was localized in the glomerular vascular pole, apparently in the juxtaglomerular apparatus (JGA). All other structures were negative for DAF. By contrast, in diseased kidneys, two types of abnormalities were detected. First, JGA-DAF was significantly decreased and this abnormality correlated with the pathologic diagnosis and with the presence of C3, IgM and/or fibrinogen in the glomeruli. Second, DAF was present in the glomerular mesangium (67%), renal interstitium (68%) and/or blood vessels (38%). The presence of DAF in the mesangium and interstitium of the kidney correlated with each other and correlated with C1q and C3 deposition in the glomerulus. Finally, vascular DAF was significantly more common in patients with electron dense deposits in the glomeruli. In summary, DAF is present in the normal kidney and is located exclusively in the glomerular vascular pole. In diseased kidneys, DAF tends to be lost from the JGA but is often present in glomerular mesangium, interstitium and blood vessels. This pattern is specially prominent in patients demonstrating complement deposition in the glomerulus. We speculate that kidney DAF may play a role in protecting the kidney against the products of complement activation.

CD55 Antigens↗
PubMed1989

Current concepts in proteinuria.

Proteinuria, long recognized as a sign of renal disease, is a common laboratory abnormality in children and adults. Proteinuria may be transient or persistent; when persistent, the cause must be determined. Proteinuria may be primarily glomerular or tubular in origin. Glomerular proteinuria is usually an important concern. Tubular proteinuria often indicates the presence of tubulointerstitial or obstructive renal disease. Screening tests are available to detect albumin (the major protein in glomerular proteinuria), but there are no simple tests for immunoglobulin light chains and low-molecular-mass proteins, which predominate in overflow proteinuria and tubular proteinuria. These small proteins can only be detected by more sophisticated assays such as electrophoresis, isoelectric focusing, and chromatography. The association of glomerular and tubular types of proteinuria with specific disorders is reviewed in this paper, and current concepts in laboratory methodology for the study of proteinuria are summarized.

Humans↗
PubMed1989

Anionic sites in the human kidney: ex vivo perfusion studies.

Heparan sulfate-proteoglycan (HS-PG) anionic sites located in the glomerular basement membrane (GBM) are thought to contribute to glomerular permselectivity in man. The number and distribution of HS-PG anionic sites in the GBM and mesangial matrix of seven normal human kidneys and three kidneys from children with congenital nephrotic syndrome (CNS) were evaluated by ex vivo perfusion of polyethyleneimine (PEI; Mr 40,000 to 60,000). In the normal kidneys lamina rara externa (LRE) anionic sites (21.8 +/- 2.4 per 1000-nm actual GBM length) were well labeled and similar to those obtained by immersion staining of fixed tissue with Mr 1200 PEI. Lamina rara interna (LRI) anionic site number (22.0 +/- 2.6 per 1000-nm GBM) and appearance were better demonstrated by PEI perfusion than by the immersion technique. PEI perfusion also demonstrated regularly arranged (60 to 120 nm apart) mesangial matrix anionic sites (20- to 30-nm diameter) at 4.09 +/- 0.59 x 10(3) sites per nm2 matrix. PEI perfusion of three kidneys from children with CNS demonstrated decreased (16.3 +/- 1.9 per 1000-nm GBM) LRE anionic sites and normal LRI anionic sites (22.0 +/- 3.5 per 1000-nm GBM). Mesangial volume was increased, and mesangial anionic sites were less frequent (3.24 +/- 0.42 x 10(3) per nm2 matrix) and irregular in size in the children with CNS.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Cyclosporine nephrotoxicity in spontaneously hypertensive rats.

In the present study, we investigated the combined, nephrotoxic effects of cyclosporine (CsA) and hypertension in young, spontaneously hypertensive rats (SHR). After 4 weeks of CsA therapy, SHR, compared with oil-treated SHR, showed an acceleration in the development of hypertension, mild renal insufficiency, and the accumulation of periodic-acid-Schiff-positive (PAS [+]) material in periglomerular arterioles. By electron microscopy, PAS(+) material was composed of intracytoplasmic inclusion bodies consistent with the accumulation of renin granules. This finding was demonstrated in SHR after 4 weeks of CsA therapy but not after 8 weeks of therapy. By contrast, CsA had no significant effect on blood pressure in Wistar-Kyoto rats, a normo-tensive control. To investigate the effect of unilateral nephrectomy (UNx) on the development of renal histopathologic changes in this model, SHR were subjected to uninephrectomy and CsA or oil therapy. UNx accelerated the development of hypertension in all SHR groups. SHR subjected to UNx demonstrated no renal histopathologic changes after CsA or oil treatment. In conclusion, CsA accelerates the development of hypertension in SHR, and this effect is probably renin-mediated. The combination of UNx and CsA therapy in the SHR does not result in significant renal histologic damage.

Animals↗
PubMed1987

Combined nephrotoxic effects of cyclosporine and endotoxin.

This study presents experimental evidence that cyclosporine (CsA) potentiates the nephrotoxicity of endotoxin. This study was motivated by clinical observations in 4 cyclosporine (CsA)-treated renal allograft recipients who developed severe, and sometimes irreversible, nephrotoxicity after infections. CsA or vehicle was administered intramuscularly to rabbits for 5 days, and subsequently both groups of animals received one dose of endotoxin intravenously. Compared with controls, CsA-treated animals demonstrated significantly higher elevations of blood urea nitrogen and serum creatinine 24 hr after endotoxin. By contrast, both groups of animals developed similar degrees of thrombocytopenia. Histologic evaluation of kidney tissues 24 hr after endotoxin revealed significantly greater tubular toxicity and a higher glomerular polymorphonuclear leukocyte (PMN) infiltration in CsA-treated animals. Semiquantitative scores of tubular damage correlated directly with the mean number of PMN/glomeruli in both groups of animals. Immunofluorescent microscopy of kidney tissues was negative for fibrinogen and for complement deposition in both CsA and control groups. We conclude that CsA enhances endotoxin nephrotoxicity in rabbits. This effect does not appear to be mediated by activation of coagulation factors. However, a role for PMN is suggested. CsA should be used with caution in patients with deteriorating renal function who are suspected of having severe bacterial infections.

Animals↗
PubMed1986

Glomerular filtration rate in children: validation and longitudinal use of determination from the 99mTc DTPA renogram.

The glomerular filtration rate (GFR) was estimated from the technetium diethylenetriaminepentacetic (99mTc DTPA) renogram by empirically correlating the renogram and clearance of the tracer as measured by plasma disappearance kinetics. To expand the potential application of this technique from its original description, minor changes in methodology were made; a new regression was generated with 30 subjects, and that formula was then validated prospectively. For the 50 children and adolescents in the prospective series whose GFR normalized for surface area (NGFR = GFR X 1.73 m2/SA; SA, surface area) was less than 120 mL/min/1.73 m2; renal function was estimated with a mean residual error of 8.0 mL/min/1.73 m2, and a mean relative error of 11%. These results are at least as good as those in the initial report, thus validating this method in a prospective series. To examine the use of this method longitudinally, 129 examinations were reviewed in 55 subjects who had NGFR estimated from the renogram (estimated) on at least two occasions. For 28 sets of serial examinations, NGFR was also measured by the plasma disappearance of 99mTc DTPA (measured). The true change in function for each set of serial examinations was defined as the increment for whichever method (estimation or measurement) was more stable. The mean longitudinal errors were 2.1 and 4.8 mL/min/1.73 m2 for measured and estimated NGFR, respectively. The increments in NGFR for these methods were correlated with a regression line near identity and r = .852. This indicates that a change in estimated NGFR reflects a change in measured NGFR of similar magnitude. This method can accurately estimate GFR from the 99mTc DTPA renogram, and it can be used longitudinally to follow children with renal disorders.

Adolescent↗
PubMed1986

Glomerular basement membrane anionic charge site changes early in aminonucleoside nephrosis.

Alterations of glomerular basement membrane (GBM) anionic (charge sites, CSs) in the development of proteinuria in a model of idiopathic nephrotic syndrome in man (puromycin aminonucleoside nephrotic syndrome [PAN] in the rat) were assessed quantitatively and sequentially early after disease induction. GBM CSs (known to consist mainly of heparan sulfate-rich proteoglycans) were stained in vivo and, in a separate group of animals by an in vitro method, with the cationic marker polyethyleneimine (PEI) studied by electron microscopic examination. Four hours after administration of PAN, there was a significant decrease in GBM lamina rara externa CSs: 18 +/- 0.7 versus 22.0 +/- 2.2 per 1000 nm GBM in controls by PEI injection and 17.2 +/- 2.7 versus 21.1 +/- 1.6 per 1000 nm GBM in controls by PEI in vitro staining. This CS alteration coincided with changes in glomerular epithelial cell morphologic characteristics (increased cytoplasmic organelles and rough endoplasmic reticulum) and preceded the detection of foot process broadening (at 24 hours) and increased urinary albuminuria (suggested at 12-24 hours, statistically significant at 36-48 hours). These results suggest that GBM CS-heparan sulfate proteoglycan alterations consisting of either decreased number and/or less anionic charge occur early in PAN and support a role for glomerular epithelial cell maintenance of GBM CS for normal glomerular function.

Animals↗
PubMed1984

Congenital nephrotic syndrome: evolution of medical management and results of renal transplantation.

We analyzed the clinical course, pathologic findings, and results of aggressive medical management and renal transplantation in 41 infants with onset of nephrotic syndrome in the first 3 months of life. All but one infant with congenital onset failed to thrive and had progressive renal insufficiency; 17 were given steroids or cytotoxic drugs or both, without benefit. Severe bacterial infections occurred in 85% of the infants, pyloric stenosis in 12%, gastroesophageal reflux in 8%, and thrombotic events in 10%. All children prior to the era of renal transplantation died before 4 years of age. The last 24 infants received aggressive medical management, which allowed renal transplantation in 17. Two-year patient and graft survival rates were 82% and 71%, respectively. There was no recurrence of the nephrotic syndrome in the children who underwent transplantation. All but one surviving infants has had normal or accelerated growth, although mean height for the group is 3.1 SD below the mean. School and social performance has been normal in 80%. Thus intensive medical therapy combined with renal transplantation offers a very good opportunity for survival with an acceptable quality of life for infants with congenital nephrotic syndrome.

Child Development↗
PubMed1983

Heparan sulfate--rich anionic sites in the human glomerular basement membrane. Decreased concentration in congenital nephrotic syndrome.

Recent work suggests that the normal barrier to penetration of the renal glomerular basement membrane by anionic plasma proteins may depend in part on the existence of negatively charged sites within the membrane. We describe an in vitro cytochemical method for the quantitative demonstration of anionic sites in the normal human glomerular basement membrane. In five normal subjects, ranging in age from 10 days to 57 years, the sites were distributed at regular intervals in the lamina rara externa, with a frequency of 23.8 +/- 6.8 sites per 1000-nm length of membrane. A similar distribution was observed in the basement membranes from three normal human fetuses. Ex vivo perfusion of one cadaver kidney revealed a similar distribution of anionic sites. The number of anionic sites in the glomerular basement membranes of five patients with the congenital nephrotic syndrome was reduced to 8.9 +/- 3.7 (P less than 0.001). Prior incubation of sections of normal kidney in purified heparinase resulted in a marked reduction in the number of anionic sites. We conclude that congenital nephrosis results from failure of heparan sulfate--rich anionic sites to develop in the lamina rara externa of the glomerular basement membrane.

Anions↗
PubMedDate not supplied

Anionic charge sites in the kidney: comparison of two diabetic rat models.

The distribution and appearance of anionic charge sides (ACS) in the glomerular basement membrane (GBM) and mesangium were studied in two different animal models of diabetes mellitus (DM), the obese Zucker rat as an animal model of type 2 diabetes mellitus (DM) and streptozocin-induced Sprague-Dawley rat as an animal model of type 1 DM. Four obese Zucker rats (ZR) and four Sprague-Dawley rats were analyzed for the following parameters: number of ACS per length of lamina rara externa (LRE), (ACS/LRE); number of ACE per length of lamina rara interna (LRI) (ACS/LRI); percent of mesangial matrix as ACS (%MMACS); percent of LRE as ACS (%LREACS); percent of LRI as ACS (%LRIACS); length of ACS in LRI (LACSLRI); length of ACS in LRE (LACSLRE); width of ACS in LRI (WACSLRI); width of ACS in the LRE (WACSLRE); area of ACS in the LRI (AACSLRI); and the area of ACS in the LRE (AACSLRE). Statistical analyses include a one-way analysis of variance (ANOVA), Pearson's correlation coefficient, and stepwise multiple regression. This study confirms that a loss of ACS occurs as proteinuria develops in a variety of animal models. The majority of the ACS were more prominently localized, and thus lost form the LRE of the GBM in DN. This study also demonstrated that defined alterations in the glomerular ACS can be identified early in the evolution of DN in both animal models, and that the similarity of the changes in the ACS suggest that a common pathophysiologic mechanism induced the changes in both animal models.

Animals↗
PubMedDate not supplied

Aerobic training and diabetic nephropathy in the obese Zucker rat.

The effects of aerobic exercise training on diabetes control and the development of renal microvascular disease were studied in the obese Zucker rat, an animal model of noninsulin dependent diabetes mellitus (NIDDM). Training consisted of 12 weeks of treadmill running, beginning at six weeks of age. Eight trained obese Zucker rats were compared to 15 obese sedentary controls and to 22 sedentary lean nondiseased littermates. Fasting blood glucose, percent of glycated hemoglobin, serum insulin, serum total cholesterol, body weight and kidney weight, creatinine clearance, urine total protein excretion, urine albumin excretion, and morphometric analyses of cortical glomeruli by light and electron microscopy were performed to evaluate metabolic control, renal function, and structure. Training was associated with less albuminuria, less mesangial volume expansion, and less glomerular basement membrane thickening compared to obese sedentary NIDDM animals. These results suggest that exercise training reduces the glomerular ultrastructural lesions and attenuates the albumin excretion rate in this rat model of obesity-related diabetes.

Aerobiosis↗