Improving Resident Self-Efficacy in Tracheostomy Management Using a Novel Curriculum.

Introduction: Patients receiving pediatric tracheostomy have significant risk for mortality due to compromised airway. Timely management of airway emergencies in children with tracheostomies is an important clinical skill for pediatricians. We developed this curriculum to improve residents' self-efficacy with tracheostomy management. Methods: We collected baseline data on 67 residents from two hospitals while creating a blended curriculum with video-based instruction on routine tracheostomy change and team management of tracheostomy emergency. Forty residents enrolled in the curriculum. During an ICU rotation, they received face-to-face instruction on routine tracheostomy change in small groups, followed by assessment of managing a tracheostomy emergency during a simulation. A video completed prior to the simulation took 9 minutes, the routine tracheostomy change didactic session took 15 minutes, and the simulation instruction was completed in 10-15 minutes. We collected feedback on the effectiveness of the curriculum from the participants. Results: All 107 residents from the baseline and intervention groups completed the self-efficacy survey. The intervention group had significantly higher changes in scores across all self-efficacy domains than the baseline group. On the curriculum feedback survey, residents rated the curriculum very highly, between 4.4 and 4.8 on a 5-point Likert scale. Discussion: Our blended curriculum increased learners' self-efficacy and promoted learner competence in tracheostomy management. Residents scored more than 80% across all aspects of simulation assessment and reported higher self-efficacy scores following our curricular intervention.

Preparedness of pediatric residents for fellowship: a survey of US neonatal-perinatal fellowship program directors.

OBJECTIVE: To evaluate the preparedness of pediatric residents entering accredited neonatal-perinatal medicine (NPM) fellowships in the United States. STUDY DESIGN: A multi-domain, validated survey was distributed to Program Directors (PDs) of US NPM fellowship programs. The 47-item survey explored 5 domains: professionalism, independent practice, psychomotor ability, clinical evaluation, and academia. A systematic, qualitative analysis on free-text comments was also performed. RESULTS: Sixty-one PDs completed the survey, for a response rate of 62% (61/98). For entering fellows, PDs assessed performance in professionalism positively, including 76% as communicating effectively with parents and 90% treating residents/house-staff with respect. In contrast, most PDs rated performance in psychomotor abilities negatively, including 59% and 79% as deficient in bag-and-mask ventilation and neonatal endotracheal intubation, respectively. Although 62% of PDs assessed entering fellows positively for genuine interest in academic projects, fewer than 10% responded positively that entering fellows understood research protocol design, basic statistics, or were capable of writing a cohesive manuscript well. Thematic clustering of qualitative data revealed deficits in psychomotor ability and academia/scholarship. CONCLUSIONS: On the basis of the perspective of front line educators, graduating pediatric residents are underprepared for subspecialty fellowship training in NPM. To provide the best preparation for pediatric graduates who pursue advanced training, changes to residency education to address deficiencies in these important competencies are warranted.

Self-Management and Transition Readiness Assessment: Development, Reliability, and Factor Structure of the STARx Questionnaire.

INTRODUCTION: The Self-Management and Transition to Adulthood with Rx=Treatment (STARx) Questionnaire was developed to collect information on self-management and health care transition (HCT) skills, via self-report, in a broad population of adolescents and young adults (AYAs) with chronic conditions. METHODS: Over several iterations, the STARx questionnaire was created with AYA, family, and health provider input. The development and pilot testing of the STARx Questionnaire took place with the assistance of 1219 AYAs with different chronic health conditions, in multiple institutions and settings over three phases: item development, pilot testing, reliability and factor structuring. RESULTS: The three development phases resulted in a final version of the STARx Questionnaire. The exploratory factor analysis of the third version of the 18-item STARx identified six factors that accounted for about 65% of the variance: Medication management, Provider communication, Engagement during appointments, Disease knowledge, Adult health responsibilities, and Resource utilization. Reliability estimates revealed good internal consistency and temporal stability, with the alpha coefficient for the overall scale being .80. The STARx was developmentally sensitive, with older patients scoring significantly higher on nearly every factor than younger patients. CONCLUSION: The STARx Questionnaire is a reliable, self-report tool with adequate internal consistency, temporal stability, and a strong, multidimensional factor structure. It provides another assessment strategy to measure self-management and transition skills in AYAs with chronic conditions.

Dietary modifications alone do not improve bone mineral density in children with idiopathic hypercalciuria.

Prior cross-sectional studies have demonstrated an association between hypercalciuria and low bone mineral density (BMD) in children and adults. However, the natural history of BMD in children with hypercalciuria and its response to therapy has not been evaluated. The objective of this retrospective study was to determine the change over time in lumbar (L1 - L4) BMD Z-score measured on sequential DXA scans in 19 children with hypercalciuria treated with dietary recommendations without (n = 12, Group A) and with citrate (n = 7, Group B). The mean lumbar bone density Z-score/year decreased in Group A (-0.11 ±/0.41) indicating that children with hypercalciuria lose L1 - L4 BMD over time. In contrast, the L1 - L4 BMD Zscore/ year increased in Group B (0.19 ± 0.38) suggesting that pharmacologic therapy may reverse this trend. Similarly 75% of patients in Group A, but only 29% patients in Group B had a decrease in L1 - L4 BMD. There was a definite, although not significant, trend towards improved mean bone mineral density Z-score per year and a lower percentage of patients with a decreased Z-score in hypercalciuric children treated with potassium citrate. Our findings suggest the possibility that dietary recommendations alone is not adequate as the bone mineral density of children with hypercalciuria will decrease over time, potentially increasing the risk for osteoporosis as an adult.

The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry.

PURPOSE: Well-functioning vascular access is essential for the provision of adequate CRRT. However, few data exist to describe the effect of catheter size or location on CRRT performance in the pediatric population. METHODS: Data for vascular access site, size, and location, as well as type of anticoagulant used and patient demographic data were gathered from the ppCRRT registry. Kaplan-Meier curves were generated and then analyzed by log-rank test or Cox Proportional Hazards model. RESULTS: Access diameter was found to significantly affect circuit survival. None of the 5 French catheters lasted longer than 20 hours. Seven and 9 French, but not 8 French, catheters fared worse than larger diameter catheters (p=0.002). Circuits associated with internal jugular access survived longer than subclavian or femoral access associated circuits (p<0.05). Circuit survival was also found to be favorably associated with the CVVHD modality (p<0.001). CONCLUSIONS: Functional CRRT circuit survival in children is favored by larger catheter diameter, internal jugular vein insertion site and CVVHD. For patients requiring catheter diameters less than 10 French, CRRT circuit survival might be optimized if internal jugular vein insertion is feasible. Conversely, when a vascular access site other than the internal jugular vein is most prudent, consideration should be given to using the largest diameter catheter appropriate for the size of the child. The CVVHD modality was associated with longer circuit survival, but the mechanism by which this occurs is unclear.

The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: design, development and data assessed.

Many issues plague the pediatric ARF outcome literature, which include data only from single center sources, a relative lack of prospective study, mixture within studies of renal replacement therapy modality without stratification and inconsistent use of methods to control for patient illness severity in outcome analysis. Since January 2001, the Prospective Pediatric CRRT (ppCRRT) Registry Group has been collecting data from multiple United States pediatric centers to obtain demographic data regarding pediatric patients who receive CRRT, assess the effect of different CRRT prescriptions on circuit function and evaluate the impact of clinical variables on patient outcome. The aim of the current paper is to describe the ppCRRT Registry design, review the decision process and rationale for the options chosen for the ppCRRT format and discuss the analysis plan and future projects envisioned for the ppCRRT Registry.

Proximal tubular epithelial hyperplasia in patients with chronic glomerular proteinuria.

BACKGROUND: Proteinuria is known to affect the proximal tubular epithelial structure and function. The present study tested the hypothesis that chronic proteinuria leads to hyperplasia of proximal tubular epithelium. METHODS: This hypothesis was tested by morphometric analysis of the renal biopsy specimens in two groups of patients. Group A (N = 15) was composed of patients with chronic glomerular proteinuria who, for clinical indications, underwent renal biopsy of their native kidneys on two separate occasions. The proteinuria was sustained during the first and second renal biopsies in all but two of the patients with minimal change nephrotic syndrome who experienced transient remission. Group B (N = 10) was composed of patients with little or no proteinuria who underwent renal biopsy because of unexplained hematuria and whose renal biopsy showed only thin glomerular basement membrane (GBM) disease. RESULTS: In Group A, the mean number of epithelial cell nuclei per proximal tubule cross-section increased significantly from the first to the second renal biopsy (11.0 +/- 2.7 vs. 13.0 +/- 2.2, P = 0.005, paired t-test). Also, those with severe proteinuria showed proximal tubules with reactive epithelium (large pale nuclei with a high nucleus to cytoplasm ratio) and marked hyperplasia (double and triple layers of epithelium). Such changes were not seen in group B renal biopsies. Compared with group A biopsies, group B biopsies showed a lower mean value for proximal tubular epithelial cell nuclei per tubular cross-section (P = 0.056) and a higher mean proximal tubular volume (P = 0.049). As a consequence, the mean number of nuclei per relative tubular volume was significantly greater in group A compared with group B (0.55 +/- 0.14 vs. 0.40 +/- 0.06, P = 0.003, by Wilcoxon rank sum). CONCLUSIONS: Chronic heavy proteinuria is associated with hyperplasia of proximal tubular epithelium and contraction of proximal tubular volume. These events may impair glomerular filtration and represent another mechanism of progression of renal disease.

Infarction of the choledochus, liver, gallbladder, and pancreas: a unique complication of the hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is associated with multiple nonrenal manifestations. A unique case is described of a 3-year-old boy who presented with a classic diarrheal prodrome followed by massive necrosis of the biliary tree and common bile duct, pancreas, and the left lobe of his liver. This complication of HUS has not been reported in the English-language literature.

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.

Efficacy of amlodipine in pediatric patients with hypertension.

We designed a study to determine the efficacy and safety of amlodipine given once daily in the pediatric population. Twenty-one patients (mean age 13.1 years) with either essential (n=160) or renal (n=5) hypertension, and newly diagnosed (n=15) or poorly controlled or intolerant on existing antihypertensive therapy (n=6), were included. Patients received amlodipine once daily at a starting mean dose of 0.07+/-0.04 mg/kg per day. The total daily dose of amlodipine was increased 25%-50% every 5-7 days if the mean home blood pressure measurements (HBPM) were above the 95th percentile for age and gender. A baseline followed by a repeat 24-h ambulatory blood pressure monitor study (ABPM) was performed in 20 patients when the mean HBPM was below the 95th percentile goal. The mean titrated dose required to control BP was 0.29+/-0.11 mg/kg per day for those < 13 years, 0.16+/-0.11 mg/kg per day for those > or = 13 years, 0.23+/-0.14 mg/kg per day for essential, hypertension and 0.24+/-0.13 mg/kg per day for renal hypertension. The ABPM demonstrated that amlodipine provided effective BP control as primary therapy in 14 essential patients. Adverse effects included fatigue (n=6), headache (n=5), facial flushing (n=4), dizziness (n=3), edema (n=3), abdominal pain (n=3), chest pain (n=2), nausea (n=1), and vomiting (n=1). Quality of life appeared to improve during therapy. Amlodipine was an effective once daily antihypertensive agent with an acceptable safety profile. Higher doses of amlodipine were required for younger patients, and monotherapy was effective in patients with essential hypertension.

Evaluation of hematuria, proteinuria, and hypertension in adolescents.

Signs or symptoms of renal disease in adolescents deserve prompt attention and appropriate evaluation. Adolescents are susceptible to a variety of urinary tract disorders. The key issue in the evaluation of hematuria or proteinuria in adolescents is the existence of concomitant signs of renal disease. For isolated hematuria or proteinuria, demonstration of persistence and a reasoned evaluation are in order. Hypertension in adolescents must be carefully documented and, when present, considered seriously. The fact that most teens with persistent elevated blood pressures have essential hypertension is still a great concern because for most of these adolescents the hypertension will be lifelong and, if left untreated, can be associated with significant morbidity and mortality in the adult years.

Effect of enalapril therapy on glomerular accumulation of immune complexes and mesangial matrix in experimental glomerulonephritis in the nonhuman primate.

The present study is a prospective, controlled, blinded trial of enalapril therapy in experimental immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate (cynomolgus monkey [CYN]). Two groups of CYNs were studied: those with established GN (study A) and those in which GN was being induced (study B). In study A, 12 CYNs had GN established by 8 or 10 weeks of daily intravenous infusion of bovine gamma-globulin (BGG). These CYNs were then assigned to either 4 weeks of daily oral enalapril therapy (n = 6) or daily oral placebo therapy (n = 6). The daily BGG infusions were continued during the 4 weeks of enalapril or placebo therapy. At the start of the enalapril/placebo protocol, the two groups were similar with respect to proteinuria and level of precipitating antibody to BGG, which determined the daily BGG dose. Renal biopsy was performed in each CYN at the start and end of the 4-week period of enalapril/placebo protocol. In study B, 15 normal CYNs were immunized to BGG over a period of 4 weeks. The CYNs were then assigned to daily oral enalapril therapy (n = 8) or placebo therapy (n = 7) based on level of precipitating antibody to BGG. At this point, daily intravenous BGG was begun along with daily enalapril or placebo for 8 weeks. Renal biopsy was performed in each CYN before and at the end of this 8-week period. In study A, enalapril therapy was associated with a significant decrease in mesangial matrix volume (mean change, -27.7%; P = 0.031) and a trend toward decreased mesangial matrix deposits (mean change, -34.1%; P = 0.188). By contrast, in CYNs receiving placebo therapy, mesangial matrix volume increased compared with the enalapril group (P = 0.002) and mesangial deposits were unchanged. In study B, both the enalapril and placebo groups showed significant increases in mesangial matrix volume, mesangial deposits, mesangial cell volume, and capillary wall deposits during the 8 weeks of daily BGG infusion. However, none of the differences between the groups achieved statistical significance. Changes in mesangial cell volume and capillary wall deposits were also evaluated in study A and study B, but were not found to be different between the enalapril and placebo groups. In both study A and study B, blood pressure was lower in the enalapril groups. In conclusion, in the initial phase of IC-GN induction (0 to 8 weeks), enalapril therapy does not significantly influence the glomerular accumulation of mesangial matrix or immune deposits. However, in established IC-GN (after 8 weeks of GN induction), enalapril therapy significantly decreases the further accumulation of mesangial matrix and may decrease the further accumulation of mesangial deposits. Whether this benefit of enalapril therapy was related to lower blood pressure or to other effects of angiotensin-converting enzyme (ACE) inhibition was not determined in this study.

Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells.

In the pathogenesis of the hemolytic uremic syndrome (HUS), endothelial damage of glomeruli and arterioles of the kidney appears to play a central role. Previous studies have shown that verocytotoxin-1 (VT-1) cytotoxicity on human vein endothelial cells require additional stimuli, in particular the inflammatory mediator tumor necrosis factor alpha (TNF alpha). In this study the effects of VT on human glomerular microvascular endothelial cells (GMVEC) were examined. A reproducible method was developed for the isolation and purification of large numbers of highly purified GMVEC. The obtained GMVEC were over 99% pure; their endothelial origin was demonstrated by the expression of the endothelial antigens von Willebrand factor, EN-4, PECAM-1 and V,E-cadherin. Upon stimulation with TNF alpha the cells expressed the endothelial-specific adhesion molecule E-selectin. A limited number of fenestral structures was observed by scanning electron microscopy (SEM), suggesting glomerular origin of the endothelial cells. Cytotoxicity of VT-1 to GMVEC was evaluated by determination of the number of viable adherent cells and by assay of overall protein synthesis after exposure to varying concentrations of VT-1. In non-stimulated GMVEC, cytotoxicity of VT-1 was inversely related to the degree and duration of confluence, subconfluent cells being the most sensitive. In highly confluent GMVEC, VT cytotoxicity required pre-exposure of the cells to the inflammatory mediator TNF alpha, which induced an increase in the number of VT receptors on GMVEC. Thin layer chromatography of extracted glycolipids from the GMVEC showed binding of VT-1 to globotriaosylceramide (Gb3), known to be the functional receptor for VT. There were no major differences in protein synthesis inhibition with equal concentrations VT-1 and VT-2. In conclusion, in this study we provide a reproducible method to isolate, purify and culture well characterized human GMVEC on a routine basis. In vitro studies with these GMVEC demonstrate that VT cytotoxicity depends on the degree of confluence and the additional preexposure to the inflammatory mediator TNF alpha. These observations provide further insight into the complex events that may occur in glomeruli in the pathogenesis of HUS.

A prospective comparison of bone density in adolescent girls receiving depot medroxyprogesterone acetate (Depo-Provera), levonorgestrel (Norplant), or oral contraceptives.

OBJECTIVE: To examine bone density among adolescents receiving different forms of hormonal contraception along with that of control subjects. METHODS: Baseline and 1-year measures of lumbar vertebral bone density were obtained in girls receiving depot medroxyprogesterone acetate (Depo-Provera) (n = 15), levonorgestrel (Norplant) (n = 7), or oral contraceptives (n = 9) and in girls receiving no hormonal treatment (n = 17). In a subsample of Depo-Provera users (n = 8), Norplant users (n = 3), and control subjects (n = 4), bone density measurements were repeated after 2 years. Bone density was measured by dual-energy x-ray absorptiometry. RESULTS: Body mass indexes, level of pubertal development, substance use, and reproductive histories were not significantly different among the groups. More black girls were represented in the initial Depo-Provera group (p < 0.02), girls in the Norplant group exercised more hours per week (p < 0.02), and control subjects were older (p < 0.01) than those in the other groups. These variables did not significantly affect bone density results. After 1 year, bone density decreased 1.5% in Depo-Provera users, compared with increases of 2.5% in Norplant users, 1.5% in oral contraceptive users, and 2.9% control subjects (p < 0.02). After 2 years, bone density increased a total of 9.3% in Norplant users and 9.5% in control subjects but decreased a total of 3.1% in Depo-Provera users (p < 0.0001). CONCLUSION: These data suggest that Depo-Provera may, at least temporarily, suppress the expected skeletal bone mineralization in adolescents, whereas Norplant and oral contraceptives are associated with the expected increase in bone density in this population.

PIP: In Ohio, data on 31 postmenarcheal women, 12-21 years old and using hormonal contraception (Norplant = 7, Depo Provera = 15, and oral contraceptives [OCs] = 9) were compared with data on 17 controls of similar age to prospectively examine lumbar bone density in girls before and after 1 and 2 years of hormonal contraceptive use and to compare the results with young women not using hormonal contraceptives. The subjects attended a general adolescent clinic at Children's Hospital in Columbus. There was an insufficient number of OC users at 2 years, so they were not included in second year analyses. Initial height and weight were significantly associated with bone density values (p 0.05). Weight accounted for the most variance both at baseline (p 0.001) and after 1 year of treatment (p 0.01). At baseline and 1 year, bone density values between patient groups were not significantly different. At 2 years, however, Norplant users had higher bone density than Depo- Provera users and controls (1.308 vs. 1.004 and 1.087, respectively; p 0.01). After 1 year, Depo-Provera users experienced a decrease (1.53%) in bone density while Norplant users, OC users, and controls experienced an increase in bone density (2.46%, 1.52%, and 2.85%, respectively). The change in bone density between Depo-Provera users and controls was significant (p 0.02). At 2 years, Depo Provera users experienced a decrease in bone density while Norplant users and controls experienced an increase (-3.12% vs. 9.33% and 9.49%, respectively; p 0.0001). This study is important because 50% of adult bone mass is accrued during adolescence. In fact, bone mass peaks during adolescence. It is not known whether bone loss during Depo Provera use is reversible after treatment discontinuation. These findings show that Depo Provera inhibits skeletal bone mineralization in adolescents, at least temporarily, while Norplant and OCs appear to increase bone density.

Diabetic nephropathy in an aerobically trained rat model of diabetes.

The purpose of this study was to determine the effects of aerobic training on indices of glycemic control, blood pressure, serum lipids, and diabetic nephropathy (DN) in an animal model of insulin deficient diabetes mellitus. Thirty-four male Sprague-Dawley rats made diabetic with streptozocin were randomly assigned to a trained group or a sedentary group. Fifteen sedentary-nondiabetic rats served as a control group. The animals were trained on a treadmill at 18 m.min-1, 8 degrees incline for 120 min.d-1, 5 d.wk-1. Blood and 24 h urine collections were obtained at various intervals throughout the study. At 21 wk of age systolic blood pressure was measured and kidney tissue was obtained for light and electron microscopy. Analysis of variance was used to detect differences among the groups (P < or = 0.05). The diabetes produced in this investigation resulted in hyperglycemia, increased urine albumin and total protein excretion, elevated systolic blood pressure, increased fractional volume of the mesangium, and widening of the glomerular basement membrane in the sedentary-diabetic animals. Aerobic training significantly reduced the increase in fractional volume of the mesangium and fructosamine. Most importantly, aerobic training did not augment the renal damage seen in DN.

Complications of intestinal augmentation and substitution cystoplasty.

The content of these papers has been heavily weighted towards reconstructions performed utilizing segments of stomach. This was not done to place a value judgment on this type of reconstruction, rather it helps establish an awareness of: (1) potentially serious metabolic and gastrointestinal complications not previously reported in children and (2) particularly frequent symptomatic disturbances collectively included in the hematuria-dysuria syndrome. Recognition of problems specifically associated with a certain type of intestinal segment, as well as complications generally accompanying any form of intestinal reconstruction, will hopefully provide pediatric urologists and nephrologists with a better understanding of the issues that must be addressed in using these newer surgical techniques and focus attention on the specific indications and contraindications for incorporating intestinal segments into the urinary tract. Although long-term follow-up information still remains sparse, it appears that regular surveillance programs are required and both pediatric nephrologists and urologists need to be part of these programs.

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.

Effect of chronically increased erythrocyte complement receptors on immune complex nephritis.

Experimental studies in humans and other primates have shown that the erythrocyte (E) complement receptor Type 1 (CR1), which is unique to the primate, plays an important role in clearing immune complexes (IC) from the circulation by binding C3b/C4b opsonized immune complexes and carrying the IC to liver and spleen for disposal. The results of these acute experiments suggest that increasing E-CR1 levels chronically should protect against IC-mediated glomerulonephritis (IC-GN) induced by chronic formation of IC in the circulation. In the present study this hypothesis was tested in the cynomolgus monkey (CYN). IC-GN was induced by daily bolus intravenous infusion of BGG into immunized CYN for 8, 10, or 14 weeks. Prior to and during the daily bolus infusions of BGG, sustained differences in E-CR1 levels were achieved between the experimental group (increased E-CR1 levels) and the control group (maintained or decreased E-CR1 levels), by one of two methods: (1) Twice weekly exchange transfusion. The CYN donors were blood type compatible with the recipients and had either constitutive high E-CR1 expression (3,000 to 5,000 CR1/E) or constitutive low E-CR1 expression (< 100 CR/E). The recipients of the exchange transfusions (N = 2) had constitutive mid-level E-CR1 expression. (2) Weekly phlebotomy (PL) or sham PL. CYN with mid-level E-CR1 expression were randomly assigned to receive weekly either PL (causing increased E-CR1 expression by stimulating erythropoiesis) (N = 8) or sham PL (which has no effect on E-CR1 expression (N = 9).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-converting enzyme inhibition partially prevents diabetic organomegaly.

The present study was conducted to evaluate whether captopril prevents the organomegaly and accumulation of matrix proteins that normally accompanies the diabetic state. The following groups of rats were studied: normal rats, normal rats treated with captopril (30 mg/kg/d orally), streptozotocin diabetic rats, and diabetic rats treated with captopril. All rats were killed at 10 weeks for histologic and morphometric evaluation of tissues. Compared with the normal rats, the diabetic rats demonstrated significant hepatomegaly, nephromegaly, and cardiomegaly, and the increase in organ size was directly related to increasing levels of protein glycosylation. The development of organomegaly was partially prevented by captopril. We determined by morphometry that the hepatomegaly seen in the diabetic rats was due to an increase in cell size and number, while the nephromegaly seen in the diabetic rats was due to an increase in tubular and glomerular cell size and is associated with glomerular hypertrophy. Captopril prevented the development of hepatic and renal cell hypertrophy and glomerular hypertrophy. These effects of captopril were not associated with detectable changes in body weight or levels of glucose, protein glycosylation, glycosuria, or renal histologic changes secondary to glycosuria. The diabetic rats demonstrated significant glomerular mesangial matrix expansion, and captopril treatment partially prevented that expansion. In conclusion, captopril prevents, in part, the development of organomegaly in diabetic rats, and this effect is due mainly to the prevention of the development of cellular hypertrophy. The present findings are most consistent with a direct effect of captopril on cell metabolism during diabetes mellitus.

Platelet involvement in experimental immune complex-mediated glomerulonephritis in the nonhuman primate.

Abundant glomerular platelet deposition is a hallmark of certain animal models of immune complex (IC)-mediated glomerulonephritis (GN). By contrast, conspicuous platelet deposition is uncommon in the IC-GN seen in humans. This could result from intrinsic differences between human and animal platelets, which are known to be present. To assess whether abundant glomerular platelet deposition can occur in humans with IC-GN, the present studies were undertaken in nonhuman primates (cynomolgus monkeys, CYN), with active experimental IC-GN induced by 12 weeks of daily intravenous infusion of bovine gamma globulin (BGG). CYN are appropriate for these studies because, like humans, CYN platelets do not express the C3b receptor but do express receptors for the Fc region of IgG (FcR gamma II). Furthermore, in this model of IC-GN, which is indistinguishable from IC-GN seen in humans, it is possible to time the biopsy to coincide with a period of peak activity of the GN. The present studies proceeded as follows: ten CYN were studied before and after intravenous infusion of BGG sufficient to achieve conditions near antigen/antibody equivalence for circulating precipitating antibody to BGG. The infusion of BGG, which was given over 10 minutes, resulted in an acute reduction in circulating platelets (mean 43% +/- 5 SE, P < 0.001). However, renal biopsies performed before and five minutes after the acute reduction in circulating platelets showed that relatively few of the platelets removed from the circulation lodged in glomeruli (platelets/glomerular cross section: 0.2 +/- 0.06 before BGG vs. 0.88 +/- 0.31 after BGG, P = 0.035). In five of the CYN studied under the above protocol, autologous platelets were labeled with 111In and reinfused into the CYN just prior to the BGG infusion. These studies confirmed the paucity of platelet deposition in kidney but showed major uptake of the 111In-labeled platelets by liver and spleen (mean +/- SE 111In CPM/mg of tissue: kidney cortex 18 +/- 8, liver 132 +/- 42, and spleen 808 +/- 127, P = 0.038, comparing kidney to liver or spleen by paired t-test). Thus, the platelets removed from the circulation were taken up at the sites which are also the principal sites of IC uptake (liver and spleen), and over the time interval that coincides with the period of maximum uptake of IC by liver and spleen, after BGG infusion. In vitro studies, discussed herein, showed that BGG anti-BGG IC bind to CYN platelets via FcR gamma II.(ABSTRACT TRUNCATED AT 400 WORDS)