Stimulation of PAI-1 in rabbit anti-GBM glomerulonephritis

SUMMARY: It has previously been shown in human disease and animal models of glomerulonephritis (GN) that fibrin deposition is associated with a net reduction of glomerular fibrinolytic activity as a result of reduced expression of plasminogen activators and increased expression of plasminogen activator inhibitor type 1 (PAI-1). Conditioned media (CM) prepared from cultured glomeruli of normal rabbits and rabbits 24 (Day 1) and 96 (Day 4) h after induction of anti-GBM GN were compared for their effects on the synthesis of fibrinolytic molecules in human endothelial cells (EC). Only CM from Day 4 GN rabbits showed PAI-1 protein stimulatory activity of up to 148% ( P <0.05; n = 3) above that of untreated EC. This was also seen at the mRNA level. Glomerulonephritis Day 4 CM showed significantly higher amounts of tumour necrosis factor (TNF) and thrombin and transforming growth factor-β (TGF-β) bioactivity in comparison to glomerular CM from normal rabbits. After high performance liquid chromatography (HPLC) of Day 4 GN CM, PAI-1 stimulatory activity was found to correlate with the presence of interleukin 1 (IL-1), TNF and TGF-β. These results suggest a correlation between severity of anti-GBM GN in a rabbit model, increased PAI-1 synthesis and increased expression of TNF and TGF-β. This may potentiate glomerular fibrin and extracellular matrix deposition in anti-GBM GN, leading to glomerular crescent formation and eventual renal failure.     

Stimulation of PAI-1 in rabbit anti-GBM glomerulonephritis

It has previously been shown in human disease and animal models of glomerulonephritis (GN) that fibrin deposition is associated with a net reduction of glomerular fibrinolytic activity as a result of reduced expression of plasminogen activators and increased expression of plasminogen activator inhibitor type 1 (PAI-1). Conditioned media (CM) prepared from cultured glomeruli of normal rabbits and rabbits 24 (Day 1) and 96 (Day 4) h after induction of anti-GBM GN were compared for their effects on the synthesis of fibrinolytic molecules in human endothelial cells (EC). Only CM from Day 4 GN rabbits showed PAI-1 protein stimulatory activity of up to 148% ( P <0.05; n =3) above that of untreated EC. This was also seen at the mRNA level. Glomerulonephritis Day 4 CM showed significantly higher amounts of tumour necrosis factor (TNF) and thrombin and transforming growth factor-β (TGF-β) bioactivity in comparison to glomerular CM from normal rabbits. After high performance liquid chromatography (HPLC) of Day 4 GN CM, PAI-1 stimulatory activity was found to correlate with the presence of interleukin 1 (IL-1), TNF and TGF-β. These results suggest a correlation between severity of anti-GBM GN in a rabbit model, increased PAI-1 synthesis and increased expression of TNF and TGF-β. This may potentiate glomerular fibrin and extracellular matrix deposition in anti-GBM GN, leading to glomerular crescent formation and eventual renal failure.     

Loss of a renal graft due to recurrence of anti-GBM disease despite rituximab therapy

Abstract:  The recurrence of anti-glomerular basement membrane (anti-GBM) glomerulonephritis (GN) in renal transplants is very rare. We report on a patient that developed acute renal allograft dysfunction due to anti-GBM GN relapse 18 months after transplantation. As plasmaseperation, dose escalation of MMF, steroids and cyclophosphamids did not result in an improvement of the graft function, a therapy with the anti-CD20 antibody Rituximab was established in addition to plasmaseperation, cyclophosphamid and steroids. Although this resulted in a decrease of anti-GBM antibody titer, graft function deteriorated further and a renal replacement therapy had to be initiated.     

Important role for macrophages in induction of crescentic anti-GBM glomerulonephritis in WKY rats.

BACKGROUND: A crucial role for CD8(+) cells in induction of crescentic anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in WKY rats was demonstrated in studies showing that depletion of CD8(+) cells completely suppressed glomerular accumulation of monocytes/macrophages (Mo/Mphi), crescent formation and proteinuria. Because these studies did not definitively identify CD8(+) cells as the cause of tissue injury, we examined the roles of Mo/Mphi in the development of anti-GBM GN. METHODS: We examined correlations between the amount of urinary protein and the numbers of glomerular CD8(+) cells or Mo/Mphi in rats after administrating different doses of anti-GBM antibody (5.0, 7.5, 10.0 and 25.0 microl/100 g body weight). The roles of Mo/Mphi in induction of GN were examined in animals by depleting Mo/Mphi in the glomerulus. To do this, rats were injected intravenously with liposome-encapsulated dichloromethylene diphosphonate (liposome-MDP) from day 3 to day 7 after anti-GBM antibody injection and they were then sacrificed at day 8. RESULTS: Liposome-MDP treatment significantly reduced the number of ED-1(+) Mo/Mphi accumulated in glomeruli from 32.1 +/- 1.2 to 1.4 +/- 0.3/glomerular cross-section (mean +/- SD, P < 0.01), and the amount of urinary protein from 103.8 +/- 19.8 to 31.8 +/- 15.9 mg/day (P < 0.01), as well as the incidence of crescentic glomeruli from 91.3 +/- 2.7 to 23.3 +/- 7.6% (P < 0.01) at day 8. This treatment also reduced the number of CD8(+) cells accumulating in the glomeruli from 5.4 +/- 0.7 to 0.5 +/- 0.1/glomerular cross-section (P < 0.01). Upregulation of glomerular intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein 1 (MCP-1) mRNA expression was suppressed by Mo/Mphi depletion. CONCLUSION: These results indicate that Mo/Mphi play an important role in the induction of crescentic anti-GBM GN and glomerular injury.     

Anti-glomerular basement membrane nephritis in a 5-year-old girl

.We report a 5-year-old girl with anti-glomerular basement membrane nephritis. Her outcome was excellent with clearance of antibody and recovery of renal function 5 weeks after the start of immunosuppression and plasmaphaeresis. Received December 11, 1995; received in revised form May 16, 1996; accepted May 20, 1996     

Anesthetic management for nephrectomy in a 2-year-old girl with abdominal aortic aneurysm

We report anesthetic management for nephrectomy in an infant with aortic aneurysm. A 2-year-old girl with renovascular hypertension and abdominal aortic aneurysm, who had shown repeated episodes of heart failure, was scheduled for nephrectomy. Anesthesia was induced with sevoflurane in nitrous oxide (70%) and oxygen. During the surgery, anesthesia was maintained with sevoflurane (1.5%) in nitrous oxide (50%) and oxygen, supplemented with intermittent epidural block. The blood pressure did not show marked changes during the surgery. There was no perioperative cardiovascular complication.     

Successful management of concommitant blunt injury to the trachea, esophagus, and cervical spine in a 6-year-old girl

A 6-year-old girl sustained an unusual constellation of injuries after blunt trauma sustained in a motor vehicle accident. Transection of the trachea and esophagus were managed successfully by repair through a median sternotomy while the patient was on cardiopulmonary bypass. A cervical spinal injury was fixated with halo traction and a femur fracture with internal fixation.     

Seven-year follow-up of vanishing bone disease in a 14-year-old girl

A review of the literature revealed 91 cases of massive osteolysis since the first report by Jackson in 1838, including 31 in the maxillofacial region meeting the Heffez criteria. In seven cases, early irradiation was performed, after which no further progression of bone lysis was observed. The young female patient reported here has been followed up clinically and radiologically for 7 years after radiotherapy, during which time she has remained stable, with no progression of the osteolysis. Our experience with this patient appears to confirm that early radiotherapy with a dose of 30–40 Gy prevents further progression of the disease and can even lead to recalcification. On this basis, and provided the patient remains symptom-free, reconstructive surgery appears a viable treatment option.     

COPD exacerbations.5: management

A review of the most relevant evidence based therapeutic options currently available for the management of exacerbations of COPD.     

Anaesthesia for phaeochromocytoma removal in a 5-year-old boy

We describe the case of a 5-year-old boy with phaeochromocytoma of the left adrenal gland, treated surgically by removal of the tumour under general anaesthesia. Phaeochromocytoma is a particularly rare tumour in children and surgical excision is the definitive treatment. We discuss the clinical and laboratory characteristics of the case, the diagnostic approach, the preoperative and intraoperative management and the postoperative course.     

Urolithiasis and psoas abscess in a 2-year-old boy with type 1 glycogen storage disease

We report on a pyogenic psoas abscess secondary to an impacted calcium oxalate ureteric stone in a 2-year-old boy with glycogen storage disease type 1 (GSD-1). The patient had a drainage of the abscess through a flank incision followed by percutaneous nephrostomy and open ureterolithotomy. Metabolic acidosis, hyperuricemia, hypocitraturia, and hypercalciuria appear to be significant in the pathogenesis of urolithiasis in patients with GSD-1. Regular ultrasonography of the abdomen along with optimal metabolic control may delay or prevent urolithiasis and its complications in GSD-1 patients.     

Successful management of a large xanthine calculus by percutaneous nephrolithotomy after failed SWL in a 5-year-old boy

A 5-year-old child with a xanthine calculus resistant to SWL was made stone free by percutaneous ultrasonic lithotripsy.     

Conus ganglioglioma in a 2 1/2-year-old boy. Case report

Gangliogliomas are rare tumors, primarily seen in patients under the age of 30 years. They occur least commonly in the spinal cord. This report presents a 2 1/2-year-old boy who harbored an intramedullary conus tumor with the light microscopic appearance of a ganglioglioma. The neurobiological behavior of this tumor is yet to be determined.