Allison A. Eddy

Neurologic manifestations of pediatric systemic lupus erythematosus.

Central nervous system involvement is a common but rarely reviewed feature of pediatric systemic lupus erythematosus (SLE). We retrospectively reviewed the charts of 91 patients with pediatric SLE and using a standardized data abstraction form documented 40 patients with central nervous system (CNS-SLE) involvement. The mean age of onset of SLE was 13.3 years. In 19 patients the CNS manifestation was a presenting symptom, in 12 patients CNS involvement was present within the first year of diagnosis, and in 9 patients it took up to 7 years for CNS disease to become evident. Nineteen children (48%) manifested neuropsychiatric SLE, which included depression, concentration or memory problems, and frank psychosis. Seizures were present in 8 patients (20%), 6 had cerebral ischemic events (15%), 1 had chorea (3%), 2 had papilledema (5%), and 2 patients had a peripheral neuropathy (5%). Nine patients (22%) had severe headache consistent with lupus headache. Seven children had more than one CNS manifestation. In the investigation of CNS-SLE, computed tomography and/or magnetic resonance imaging scans were helpful in patients with focal ischemic lesions and venous sinus thrombosis. Electroencephalography was abnormal only in 33% of patients with seizure disorders and rarely helpful in patients with diffuse neuropsychiatric symptoms. Single-photon emission computed tomography scans were abnormal in most patients with neuropsychiatric SLE, especially in those with frank psychosis. The lupus anticoagulant was present in the patient with chorea and was frequently present in patients with cerebral vascular events. Long-term outcome was good: only 1 child died of cerebral hemorrhagic infarction and 3 others had significant persistent CNS deficits. The majority of patients (90%) had excellent recovery from CNS-SLE.

Cell Biology – Immunology – PathologyMultifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1–overexpressing mice

BACKGROUNDnPlasminogen activator inhibitor-1 (PAI-1) has been implicated in the pathogenesis of chronic kidney disease based on its up-regulated expression and on the beneficial effects of PAI-1 inhibition or depletion in experimental models. PAI-1 is a multifunctional protein and the mechanisms that account for its profibrotic effects have not been fully elucidated.nnnMETHODSnThe present study was designed to investigate PAI-1-dependent fibrogenic pathways by comparing the unilateral ureteral obstruction model (UUO) (days 3, 7, and 14) in PAI-1-overexpressing mice (PAI-1 tg) to wild-type mice, both on a C57BL6 background.nnnRESULTSnFollowing UUO, total kidney PAI-1 mRNA and/or protein levels were significantly higher in the PAI-1 tg mice (N= 6 to 8/group) and fibrosis severity was significantly worse (days 3, 7, and 14), measured both as Sirius red-positive interstitial area (e.g., 10 +/- 3.2% vs. 4.5 +/- 1.0%) (day 14) and total kidney collagen (e.g., 11.1 +/- 1.7 vs. 6.2 +/- 1.3 microg/mg) (day 14). By day 14, the expression of two normal tubular proteins, E-cadherin and Ksp-cadherin, were significantly lower in the PAI-1 tg mice (3.2 +/- 0.5% vs. 11.7 +/- 5.9% and 2.6 +/- 1.6) vs. 6.2 +/- 0.8%, respectively), implying more extensive tubular damage. At least four fibrogenic pathways were differentially expressed in the PAI-1 tg mice. First, interstitial macrophage recruitment was more intense (P < 0.05 days 3 and 14). Second, interstitial myofibroblast density was greater (P < 0.05 days 3 and 7) despite similar numbers of proliferating tubulointerstitial cells. Third, transforming growth factor-beta1 (TGF-beta1) and collagen I mRNA were significantly higher. Finally, urokinase activity was significantly lower (P < 0.05 days 7 and 14) despite similar mRNA levels. Gene microarray studies documented that that the deletion of this single profibrotic gene had far-reaching consequences on renal cellular responses to chronic injury.nnnCONCLUSIONnThese data provide further evidence that PAI-1 is directly involved in interstitial fibrosis and tubular damage via two primary overlapping mechanisms: early effects on interstitial cell recruitment and late effects associated with decreased urokinase activity.

Tubulointerstitial nephritis and uveitis in children and adolescents. Four new cases and a review of the literature.

Abstractu2002We identified 35 cases of tubulointerstitial nephritis and uveitis (TINU), 31 from a MEDLINE search (1966–1996) of the English literature and 4 from our hospital records (1988–1996). To meet the case definition, the patient had to be less than 18 years old and have TINU of unknown cause. Common presenting symptoms included fatigue, weight loss, fever, and abdominal pain. The uveitis was usually anterior and could occur at any time with respect to the onset of the renal disease. Common laboratory features included anemia, increased erythrocyte sedimentation rate, and decreased creatinine clearance. Most patients (33 of 35) had renal biopsies that commonly revealed an intense inflammatory interstitial infiltrate, glomerular sparing, and negative immunofluorescence studies. Of the 35 patients, 26 received systemic corticosteroid therapy (5 of 26 for eye disease); 22 had follow-up for at least 1 year; 13 of 35 patients had a recurrence of their uveitis. The outcome in all 35 cases was normal renal function with no documented visual loss. In conclusion, TINU is a unique syndrome with characteristic clinical features, laboratory changes, and renal biopsy results. Treatment is controversial, and the outcome in children, even if untreated, is excellent.

Xanthogranulomatous Pyelonephritis in Children Etiology, Pathogenesis, Clinical and Radiologic Features, and Management

matous pyelonephritis was likely first described by Schlagenhaufer’ in 1916, and the term itself was coined by Osterlind’ in 1944. It is a chronic inflammatory lesion of the kidney characterized by destruction of the renal parenchyma, which is replaced by granulomatous tissue containing lipid-laden macrophages (foam cells). Once regarded as uncommon, the condition has been reported with increasing frequency in the last few

Coagulation abnormalities in chronic peritoneal dialysis

To determine whether children treated with chronic peritoneal dialysis have a hypercoagulable state, various coagulation and fibrinolytic factor concentrations or activities were measured in 17 children undergoing chronic peritoneal dialysis. The patients had significantly increased activities of factors VII and VIII and increased concentrations of von Willebrand factor (vWF), fibrinogen, factor XIIIA and factor XIIIS compared to reference values (P<0.001 in each case). The activated partial thromboplastin time was prolonged (P<0.001) and the thrombin clotting time was decreased (P<0.05) in these children. The prothrombin time and activities of factors XII, XI, IX, X, V and II were not significantly different from control values. Protein C concentrations were similar to normal, but antithrombin III concentrations were increased (P<0.05). Within the fibrinolytic pathway, decreased concentrations of plasminogen were found (P<0.001) and the concentrations of alpha-2-antiplasmin were increased (P<0.001). The plasma albumin concentration was below 33 g/l in 13 of the 17 children. The duration of treatment with peritoneal dialysis was directly correlated with vWF concentrations (P<0.001) and inversely correlated with factor VII concentrations (P<0.01). Of these patients 2 have since had clinical thrombotic episodes. The coagulation abnormalities found may have a role in the occurrence of thrombosis complicating renal transplantation.

Demonstration by Light Microscopy of Cytomegalovirus on a Renal Biopsy of a Renal Allograft Recipient: Confirmation by Immunohistochemistry and in situ Hybridization

A 14-year-old boy with end-stage renal failure secondary to reflux nephropathy received a renal transplant and was immunosuppressed with prednisone, azathioprine, and Minnesota antilymphoblast globulin, followed by cyclosporine A. A renal biopsy was performed 43 days post-transplantation because of fever and an elevated serum creatinine. The biopsy showed a mild interstitial lymphocytic infiltrate and immunosuppression was not changed. A second renal biopsy was performed 66 days after transplantation because of a persistent elevation of the serum creatinine following a cytomegalovirus (CMV) infection. CMV inclusions were seen by light microscopy (LM) in glomerular and peritubular capillary endothelial cells and tubular epithelial cells but no viral inclusions were present on the grids examined by electron microscopy (EM). However, the inclusions seen by LM were confirmed as CMV by immunohistochemistry, using polyclonal and monoclonal antibodies to CMV, and by in situ hybridization, using a biotinylated CMV DNA probe, emphasizing the usefulness of these techniques when studies by EM are not contributory.

Intraglomerular leukocyte recruitment during nephrotoxic serum nephritis in rats

Although circulating phagocytic cells are important mediators of glomerular injury, their recruitment mechanisms are not completely understood. In this study, the intraglomerular trafficking of leukocytes was characterized in a rat model of acute glomerular injury induced by nephrotoxic serum (NTS). Polymorphonuclear (PMN) cells infiltrated, then disappeared rapidly, reaching a peak at 2 hr. By 6 hr the PMN migration had almost reversed but small numbers persisted until Day 7. The monocyte influx began almost simultaneously but was of lesser magnitude. However, the number of ED-1+ monocytes increased progressively from 60 min to reach a plateau by Day 2 and persisted to the end of the study (Day 28). Quantitation of intraglomerular Ia+ cells suggested in situ activation of monocytes within the glomeruli. Increased Ia+ cells were first evident on Day 2. By Day 5, 80% of the intraglomerular macrophages were Ia+. Complement depletion with cobra venom factor abrogated early albuminuria, delayed the initial PMN influx, but failed to attenuate monocyte migration. T lymphocytes appeared briefly between 10 min and 2 hr. In vitro proliferation study failed to demonstrate lymphocyte sensitization to glomerular basement membrane (GBM) antigens. A unique population of cells (OX19 OX8+), possibly representing natural killer cells, was present from Day 1 to Day 14. During the secondary wave of proteinuria (autologous phase), all leukocytes had disappeared except for macrophages and a small number of OX19-, OX8+ cells. A complex intraglomerular migration of leukocytes was triggered by the binding of nephrotoxic antibodies to GBM antigens. We speculate that this cascade involves several cell-to-cell interactions necessary for the full expression of glomerular injury.

Prolongation of acute renal failure in two patients with hemolytic-uremic syndrome due to excessive plasma infusion therapy

Two children with prototypic hemolytic-uremic syndrome had prolonged acute dialysis-dependent renal failure (74 and 84 days) associated with a state of hyperproteinemia induced by extensive infusion of fresh frozen plasma (283 and 307 units). We believe that the hyperproteinemia prolonged the duration of renal failure. Following cessation of plasma therapy, the hyperproteinemic state reversed, the degree of proteinuria decreased and renal function quickly recovered. Although the pathophysiological mechanism requires further evaluation, we speculate that an alteration in the colloid oncotic pressure and/or aggravation of tubulointerstitial injury due to overload-proteinuria may have increased the duration of renal failure.

The contribution of antibody-mediated cytotoxicity and immune-complex formation to tubulointerstitial disease in passive Heymann nephritis

Passive Heymann nephritis (PHN), an experimental model of membranous nephropathy, is produced by Fx1A antiserum, which also reacts with antigens on the brush border (gp 330) and basolateral membrane (gp 90) of proximal tubules. We examined tubulointerstitial disease in PHN, identifying two distinct processes occurring on the luminal and basolateral membranes, respectively. Injected antibody bound diffusely to the tubular brush border from Day 1 to Day 7, followed by sloughing of microvilli and tubular-cell regeneration. Fine granular deposits of Fx1A antibody were present along the basolateral cell membrane by Day 1. These deposits rearranged in situ, enlarged, and became more focally distributed along tubular basement membranes (TBM). Interstitial inflammation, dominated by macrophages (Ia+, ED-1+) in association with a smaller number of T-cytotoxic cells (OX19+, OX8+) began by Day 3, reached peak intensity and persisted throughout the autologous phase (to Day 21). The distribution of focal clusters of interstitial macrophages predominately in association with TBM-immune deposits was demonstrated. Complement depletion prevented proteinuria but TBM deposits developed and the interstitial inflammation was unchanged. All aspects of the tubulointerstitial disease were amplified by a second injection of Fx1A antiserum. In vitro, Fx1A antibody bound to the surface of isolated proximal tubular epithelial cells and redistributed to form clusters of immune aggregates. Anti-Fx1A-induced cytotoxicity of tubular cells was demonstrated by prelabeling cells with 2-7-bis(carboxyethyl)-5(6)-carboxyfluorescein. The degree of cytotoxicity was dependent on complement concentration and the duration of incubation at 37 degrees C. PHN induced by Fx1A antiserum causes tubular-cell injury following interactions with brush-border antigens and TBM immune-complex disease associated with interstitial inflammation. These findings may be relevant to the acute and chronic interstitial disease of human membranous nephropathy.

A study by immunofluorescence microscopy of the NC1 domain of collagen type IV in glomerular basement membranes of two patients with hereditary nephritis

The NC1 domain of the collagen type IV molecule, the major component of glomerular basement membranes (GBM), consists of dimers and 24 kilodalton (K), 26 K and 28 K monomers in man, and contains the Goodpasture antigen. Serum obtained from patients with Goodpastures syndrome has been reported not to stain GBM of most male and some female patients with hereditary nephritis (HN) by immunofluorescence (IF) microscopy. In the present study, GBM seen on the renal biopsies of 2 patients (one male and one female) with HN were examined by IF to ascertain whether NC1 monomers were detectable. Three reagents were used: a plasmapheresis fluid (PPF) obtained from a patient who was treated for anti-GBM nephritis (human anti-GBM PPF); a commercial rabbit antibody against human NC1; and a rabbit antibody raised by us against dog NC1, which cross-reacted with human NC1. All 3 reagents detected NC1 determinants in GBM of normal human kidney by IF and reacted with human NC1 by a plate-binding radioimmunoassay (RIA). The human anti-GBM PPF bound to 28 K and 26 K monomer components of NC1 by Western blotting, the rabbit anti-human NC1 antibody bound to 26 K and 24 K monomers, while the rabbit anti-dog NC1 antibody bound only to the 26 K monomer. By IF, the human anti-GBM PPF did not stain GBM of the male patient with HN, but produced segmental staining of GBM (i.e., some GBM stained, while others did not) of the female patient. In contrast, the rabbit anti-NC1 antibodies produced global staining by IF of GBM of both patients. The absence of staining (i.e., global or segmental) seen with the human anti-GBM PPF implied that the 26 K and 28 K monomers of NC1 were either absent from GBM, or were present but altered structurally, leading to a diminution in their immunological reactivity. However, the positive staining observed with the rabbit anti-NC1 antibodies implied that the 26 K monomer was actually present in GBM. Hence, we postulate that the 26 K monomer of NC1 in GBM was structurally altered, and that the 28 K monomer was either absent, or present but altered. These findings suggest that there is an abnormality of more than one monomer of NC1 in GBM of patients with HN.