Kidney disease in lupus is not always 'lupus nephritis'

In lupus erythematosus, elevated serum creatinine levels and urinary abnormalities implicate a kidney disorder, which may not always be lupus nephritis as defined by the current classification of the International Society of Nephrology/Renal Pathology Society. The signs of renal dysfunction may be caused by lupusunrelated renal injury such as drug toxicity or infection or by lupus-associated mechanisms that are not part of the classification, such as minimal change nephrotic syndrome or thrombotic microangiopathy. The latter seems to complicate lupus nephritis more frequently than previously thought. An unbiased assessment of kidney disease in lupus requires a kidney (re-)biopsy to define the appropriate management

Glomerular permeability and polyanion in Adriamycin nephrosis in the rat

Glomerular permeability and polyanion in Adriamycin nephrosis in the rat. Alterations in glomerular permeability were studied in Adriamycin-induced proteinuria in rats by measuring fractional clearances (C/GFR) of uncharged labeled dextrans of varying molecular radii (ae) and of anionic, native, and cationic horseradish peroxidases (HRP) in experimental and control animals. Experimental animals were studied between days 14 and 55 after a single intravenous dose of Adriamycin (doxorubicin), 7.5 mg/kg. Mean proteinuria in the experimental animals was 98mg/24hr. Glomerular morphology showed few changes except for epithelial cell swelling, vacuolization, and foot process obliteration, and a significant reduction of glomerular colloidal iron staining. Polyethyleneimine staining revealed a similar distribution of anionic sites in the laminae rarae interna and externa in proteinuric rats as compared with controls. Inulin clearances revealed reduction in GFR and RPF of 20 and 15%, respectively. Dextran C/GFR values showed in experimental animals a size defect for molecules with an ae exceeding 40 Å, with a four- to fivefold increase over the values found in control animals for dextrans with ae of 58 and 60 Å. The peroxidase clearances showed a slight increase in C/GFR of anionic HRP in experimental animals, as could be expected on the basis of the sieving defect, whereas the C/GFR values for native and cationic HRP were virtually unchanged, indicating an intact functional charge barrier in the proteinuric animals. The results indicate that proteinuria in this model, which morphologically resembles aminonucleoside nephrosis, is due to a sieving defect, the charge barrier being functionally intact. The results further suggest, at least in this model, that a reduction in colloidal iron reactive glomerular polyanion is not associated with a defect in the charge selective barrier function.Perméabilité glomérulaire et polyanions dans la néphrose par Adriamycine chez le rat. Les altérations de la perméabilité glomérulaire ont été édutiées chez le rat au cours de la protéinurie induite par l'adriamycine en mesurant les clearances fractionnelles (C/GFR) de dextrans neutres marqués de différents rayons moléculaires (ae), et de peroxydases de raifort anioniques, neutres, et cationiques (HRP) chez des animaux expérimentaux et contrôles. Les animaux expérimentaux étaient étudiés entre les jours 14 et 55 après une injection unique intra-veineuse d'Adriamycine (doxorubicine), 7.5mg/kg. La protéinurie moyenne chez les animaux expérimentaux était de 98mg/24hr. La morphologie glomérulaire indiquait peu de modifications excepté un gonflement des cellules épithéliales, une vacuolisation et une fusion des pédicelles, et une réduction significative de la coloration glomérulaire par le fer colloïdal. La coloration au polyéthylèneimine a révélé une distribution identique des sites anioniques dans les lamina rarae interna et externa de rats protéinuriques par rapport aux contrôles. Les clearances de l'inuline ont montré une réduction de GFR et RPF de 20 et 15%, respectivement. Les valeurs de C/GFR du dextran ont indiqué chez les animaux expérimentaux un trouble portant sur la taille pour les molécules dont ae dépasse 40 Å, avec une augmentation de quatre- à cinqfois au-dessus des valeurs trouvées chez les animaux contrôles pour des dextrans d'ae de 58 et 60 Å. Les clearances des peroxydases ont indiqué une augmentation modérée de C/GRF pour HRP anionique chez les animaux expérimentaux, comme cela était attendu sur la base d'un trouble de la filtration, tandis que les valeurs de C/GFR pour les HRP natives et cationiques étaient virtuellement inchangées, indiquant une barrière fonctionnelle de charge intacte chez les animaux protéinuriques. Ces résultats indiquent que la protéinurie dans ce modèle qui ressemble morphologiquement à la néphrose des aminonucléosides, est due à un trouble de la filtration, la barrière de charges restant fonctionnellement intacte. Ces résultats suggèrent en outre, au moins dans ce modèle, que une réduction des polyanions glomérulaires réagissant avec le fer colloïdal n'est pas associée à une anomalie de la barrière sélective aux charges

Kidney failure in mice lacking the tetraspanin CD151

The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin α3β1. Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin α3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin α3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening α3β1-mediated adhesion in podocytes

TARP as immunotherapeutic target in AML expressed in the LSC compartment

C

The Pathophysiology ofProtein-Overload Proteinur a

Alterations in glomerular function and structure were studied in protein-overload nephrosis in the rat induced by intraperitoneal administration of bovine serum albumin (BSA). Fractional clearance (C/GFR) studies using inulin and tracer proteins of different molecular size and charge revealed in proteinuric rats 1) unchanged glomerular filtration rate and renal plasma flow; 2) a 34-fold increase in C/GFR of rat serum albumin, reaching values similar to BSA; 3) a 2-fold increase in C/GFR for anionic horse radish peroxidase (HRP), but normal values for neutral and cationic HRP, and 4) an 11-and 3-fold increase for heter-THE GLOMERULAR capillary wall (GCW) constitutes a semipermeable, size-and charge-selective filter between the glomerular capillary lumen and the urinary space." 2 Under normal conditions, the ultrafiltrate is virtually devoid ofproteins. Increased permeability to plasma proteins may be caused by a number ofimmunopathologic, toxic, or hemodynamic events leading to damage ofthe endothelial and/or epithelial cells and disruption of the glomerular basement membrane (GBM).3'4 Increased passage of proteins from the capillary lumen to the urinary space has also been observed in man and in laboratory animals after parenteral administration of high amounts of proteins.5-26 Studies on experimental models of proteinoverload proteinuria have shown that increased transcapillary movement of proteins causes degenerative changes ofglomerular epithelial cells characterized by swelling, vacuolization, increased reabsorption droplets, loss of foot processes, and lifting from the underlying GBM.'1"220 Recent studies have reported on functional and structural glomerular alterations in rat models of protein-overload proteinuria, providing conflicting evidence with regard to changes in sizeand charge-selective properties ofthe GCW. In BSAinduced proteinuria sieving curves of neutral dextrans were found to be normal, suggestive ofan intact sieving filter.23 In contrast, in the same model inFrom the Departments ofPathology and Nephrology, State University ofLeiden, Leiden, The Netherlands ologous IgG and IgM, respectively. Glomerular epithelial cells showed degenerative changes, but the distribution of anionic sites in the glomerular basement membrane was found to be unaltered, as determined by polyethyleneimine binding studies. In summary, an elevation of serum albumin concentration resulted in an increased transcapillary albumin transport. This was found to lead to degenerative changes of glomerular epithelial cells with development of large pore defects, which were completely reversible. (Am J Pathol 1987, 129:64-73) creased filtration ofIgG24 and ofanionic ferritin22 was found, and morphologic studies revealed detachment of glomerular epithelium from the underlying GBM,20,26 a lesion which is usually associated with a large pore defect.27-29 Immunoelectrophoresis of urinary proteins revealed that albumin constitutes the majority of filtered proteins, but a considerable proportion of the globulin fraction also reaches the urine. 13"16,19'20 In addition, the role of hemodynamic factors, such as possibly increased flows and pressures, has not been studied in detail. This article describes pathophysiologic mechanisms in protein-overload proteinuria in female Wistar rats rendered proteinuric by daily administration ofbovine serum albumin (BSA). Hematocrits, serum total protein, rat serum albumin (RSA), and BSA concentrations were monitored during and after BSA administration. Alterations in charge-and size-selective properties of the GCW after two doses of BSA were studied by measuring proteinuria and fractiona

Human Primary Adipocytes Exhibit Immune Cell Function: Adipocytes Prime Inflammation Independent of Macrophages

BACKGROUND: Obesity promotes inflammation in adipose tissue (AT) and this is implicated in pathophysiological complications such as insulin resistance, type 2 diabetes and cardiovascular disease. Although based on the classical hypothesis, necrotic AT adipocytes (ATA) in obese state activate AT macrophages (ATM) that then lead to a sustained chronic inflammation in AT, the link between human adipocytes and the source of inflammation in AT has not been in-depth and systematically studied. So we decided as a new hypothesis to investigate human primary adipocytes alone to see whether they are able to prime inflammation in AT. METHODS AND RESULTS: Using mRNA expression, human preadipocytes and adipocytes express the cytokines/chemokines and their receptors, MHC II molecule genes and 14 acute phase reactants including C-reactive protein. Using multiplex ELISA revealed the expression of 50 cytokine/chemokine proteins by human adipocytes. Upon lipopolysaccharide stimulation, most of these adipocyte-associated cytokines/chemokines and immune cell modulating receptors were up-regulated and a few down-regulated such as (ICAM-1, VCAM-1, MCP-1, IP-10, IL-6, IL-8, TNF-α and TNF-β highly up-regulated and IL-2, IL-7, IL-10, IL-13 and VEGF down-regulated. In migration assay, human adipocyte-derived chemokines attracted significantly more CD4+ T cells than controls and the number of migrated CD4+ cells was doubled after treating the adipocytes with LPS. Neutralizing MCP-1 effect produced by adipocytes reduced CD4+ migration by approximately 30%. CONCLUSION: Human adipocytes express many cytokines/chemokines that are biologically functional. They are able to induce inflammation and activate CD4+ cells independent of macrophages. This suggests that the primary event in the sequence leading to chronic inflammation in AT is metabolic dysfunction in adipocytes, followed by production of immunological mediators by these adipocytes, which is then exacerbated by activated ATM, activation and recruitment of immune cells. This study provides novel knowledge about the prime of inflammation in human obese adipose tissue, opening a new avenue of investigations towards obesity-associated type 2 diabetes

The classification of glomerulonephritis in systemic lupus erythematosus revisited

The classification of glomerulonephritis in systemic lupus erythematosus revisited.The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involvin

Anti-neutrophil cytoplasmic antibodies:Current diagnostic and pathophysiological potential

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by rapid deterioration of renal function occurring within days or weeks together with signs of glomerulonephritis, that is, proteinuria and hematuria with cellular casts. The syndrome is, in many cases, histopathologically manifested as fibrinoid necrosis of the capillary wall with extracapillary proliferation and crescent formation [1]. This so-called necrotizing crescentic glomerulonephritis (NCGN) is seen in 5 to 15% of renal biopsies in most series [1–3]. Although it is infrequent, the importance of the condition is illustrated by the fact that most cases of NCGN, if left untreated, develop renal failure within days or weeks [1]. Based on immunohistopathology NCGN can be subdivided into three distinct categories. The first one, occurring in 2 to 20% of the cases and characterized by linear staining of the glomerular capillary wall for immunoglobulin and complement, has classically been described as anti-glomerular basement membrane (GBM) disease. It is associated with autoantibodies to structural antigens of the GBM, in particular to the first globular noncollagen domain of collagen type IV [4]. The antibodies are considered of pathogenetic significance. The second category, comprising 15 to 50% of cases, is characterized by granular deposits of immunoglobulin and complement suggesting that immune complexes are pathogenetically involved. This type occurs in conjunction with systemic autoimmune diseases such as lupus erythematosus, in cases of post-infectious glomerulonephritis, IgA nephropathy or Henoch-Schönlein purpura, or as an idiopathic variety. The third group of NCGN, occurring in 40 to 80%, demonstrates only a few or no immune deposits and is designated as pauci-immune NCGN [1–3, 5, 6]. Pauci-immune NCGN occurs as part of Wegener's granulomatosis (WG) or related conditions, or without systemic vasculitis (idiopathic NCGN). The pathophysiology of this pauci-immune type of NCGN has not been elucidated. Within the last decade, however, it has been recognized that the condition is associated with autoantibodies to cytoplasmic components of neutrophils (anti-neutrophil cytoplasmic antibodies or ANCA).ANCA were first described in 1982 by Davies et al in a few patients with segmental necrotizing glomerulonephritis [7]. Only in 1985 did it become apparent that ANCA are a sensitive and specific marker for Wegener's granulomatosis (WG) [8]. Later on, ANCA were described in patients with microscopic polyarteritis [9]. Falk and Jennette, in 1988, showed that ANCA are also associated with the idiopathic form of pauci-immune NCGN [10]. These data have now been confirmed by many groups and support the view that ANCA-associated glomerulonephritis and vasculitis is, indeed, a distinct disease category. A number of studies, in addition, have suggested that ANCA are involved in the pathophysiology of the aforementioned disorders. As ANCA, however, have recently also been detected in a wide range of inflammatory and infectious conditions, a critical reappraisal of the diagnostic significance of ANCA-testing seems justified.In this review we will evaluate the current state of ANCA-testing as well as elaborate on the pathophysiological role of the autoantibodies in necrotizing glomerulonephritis and vasculitis. Data presented recently at the Fifth International Workshop on ANCA, held in Cambridge, United Kingdom, will be included [11]. As such, it adds to previous reviews on ANCA that were published following the Second [12], Third [13], and Fourth [14] Workshops on ANCA

The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility

Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/ fibrocellular crescents; (5) percentage of interstitial fibrosis/ tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo