Centralis superior raphe, reticularis pontis nuclei, and sleep-wakefulness cycle in cats

It has been reported that circumferential mesangial interposition (CMI) is an important morphological feature suggesting the progression of glomerulosclerosis in glomerular disease. The relation between CMI and its associated lesions was investigated in various renal diseases by electron microscopy. In 276 patients, of whom the glomeruli were observed by electron microscopy, CMI was observed non-specifically in 48 patients with various glomerular diseases (IgA nephropathy, 11; non-IgA glomerulonephritis, 1; membranoproliferative glomerulonephritis, 8; membranous nephropathy, 5; lupus glomerulonephritis, 12; toxemia of pregnancy, 2; diabetic nephropathy, 7; mitomycin nephropathy, 1; and Seckel's dwarfism patients, 1). The glomeruli with CMI showed a marked increase in mesangial matrix, as well as various grades of mesangial cell proliferation. Mesangiolysis associated with subendothelial widening was observed in a lesion of CMI in most cases. This phenomenon appears to be an initial alteration that conducts proliferated cells to the peripheral portion of a capillary loop. Localized severe thinning of the glomerular basement membrane was frequently combined with CMI, particularly in IgA nephropathy patients. Endothelial cells were occasionally interposed into the widened subendothelial space. Subendothelial deposits were noticed in the CMI lesion, particularly in MPGN patients. In conclusion, in the process of glomerulosclerosis progression in various glomerular diseases, lytic and edematous changes initially occur in the mesangio-subendothelial system (mesangiolysis and subendothelial widening), then proliferating mesangial cells extend into the widened space (between GBM and endothelial cells), and reach the peripheral portion of a capillary loop.     

Renal pathology of human immunodeficiency virus infection

Renal complications of HIV infection are clinically and morphologically diverse. These may affect the glomerular, tubulointerstitial, and vascular compartments. Tubulointerstitial injury predominates in most autopsy-based studies, whereas glomerular disease is most frequently identified in biopsy-based studies. The most common glomerular lesion is HIV-associated focal segmental glomerulosclerosis and related mesangiopathies (collectively termed HIV-associated nephropathy). Increasingly, a variety of immune complex-mediated glomerular diseases such as membranoproliferative glomerulonephritis, IgA nephropathy and lupus-like nephritis, as well as hemolytic uremic syndrome/thrombotic thrombocytopenic purpura have been reported. The spectrum of tubulointerstitial lesions includes acute tubular necrosis, interstitial nephritis, diffuse infiltrative lymphocytosis syndrome, renal infection, and neoplasms including lymphoma and Kaposi's sarcoma. The pathological features of these conditions are reviewed with emphasis on clinical-pathological correlations and pathogenesis.     

Expression of endothelial and inducible nitric oxide synthase in human glomerulonephritis

The presence of nitric oxide (NO) in the kidney has been implicated in the pathogenesis of human glomerulonephritis. However, the exact type of glomerular cells that express NO synthase (NOS) and the NOS isoform involved in the local production of NO has not been identified in the human diseased kidney. We examined the expression of three isoforms of NOS, inducible NOS (iNOS), endothelial NOS (eNOS) and brain NOS (bNOS) in the renal tissue of patients with IgA nephropathy (IgAN, N = 10), lupus nephritis (LN, N = 5), membranous nephropathy (MN, N = 5) and minimal change nephrotic syndrome (MCNS, N = 5). Sections were immunostained and the correlation between the expression of each NOS and the degree of glomerular injury in that section was also examined. Normal portions of surgically resected kidneys served as controls. eNOS was present in glomerular endothelial cells and endothelium of cortical vessels in the control and diseased kidneys. iNOS was localized in mesangial cells, glomerular epithelial cells and infiltrating cells in the diseased glomeruli, whereas immunostaining for iNOS was hardly detected in control kidneys. In addition, the expression pattern of eNOS in each glomerulus was the reverse of that of iNOS. In IgAN and LN, the extent of staining for eNOS correlated negatively with the degree of glomerular injury, while the extent of staining for iNOS correlated positively with the degree of glomerular injury in the same tissues. bNOS was not detected in normal or nephritic glomeruli. Our results indicate the presence of a NO pathway in human diseased kidney, and suggest that NO derived from eNOS and iNOS may be involved in the progression of renal diseases and that NO derived from each NOS may play an important role in different way in human inflamed glomeruli.     

Oligomeric structure of type I and type II transforming growth factor beta receptors: homodimers form in the ER and persist at the plasma membrane

Transforming growth factor beta (TGF-beta) signaling involves interactions of at least two different receptors, types I (TbetaRI) and II (TbetaRII), which form ligand-mediated heteromeric complexes. Although we have shown in the past that TbetaRII in the absence of ligand is a homodimer on the cell surface, TbetaRI has not been similarly investigated, and the site of complex formation is not known for either receptor. Several studies have indicated that homomeric interactions are involved in TGF-beta signaling and regulation, emphasizing the importance of a detailed understanding of the homooligomerization of TbetaRI or TbetaRII. Here we have combined complementary approaches to study these homomeric interactions in both naturally expressing cell lines and cells cotransfected with various combinations of epitope-tagged type I or type II receptors. We used sedimentation velocity of metabolically labeled receptors on sucrose gradients to show that both TbetaRI and TbetaRII form homodimer-sized complexes in the endoplasmic reticulum, and we used coimmunoprecipitation studies to demonstrate the existence of type I homooligomers. Using a technique based on antibody-mediated immunofluorescence copatching of receptors carrying different epitope tags, we have demonstrated ligand-independent homodimers of TbetaRI on the surface of live cells. Soluble forms of both receptors are secreted as monomers, indicating that the ectodomains are not sufficient to mediate homodimerization, although TGF-beta1 is able to promote dimerization of the type II receptor ectodomain. These findings may have important implications for the regulation of TGF-beta signaling.     

Enhanced production of glomerular extracellular matrix in a new mouse strain of high serum IgA ddY mice

To investigate the relationship between high serum levels of IgA and glomerular lesions, selective mating was performed in high serum IgA ddY mice, a murine model of spontaneously developing mesangioproliferative glomerulonephritis mimicking human IgA nephropathy. The selection and mating of high IgA ddY mice were accomplished when the mice were three to four months old. In the 12th generation of high IgA ddY (HIGA) mice, significantly higher levels of serum IgA from 10 age weeks to 60 weeks (P < 0.0002 to 0.0001) were observed in comparison with BALB/c mice. Relatively high proteinuria was observed at 40 weeks of age, although hematuria was consistently negative. Microscopic observations of renal tissue disclosed a marked glomerular mesangial matrix increase and a reduction of cell proliferation with age by both semiquantitative and morphometric analyses with moderate tubulointerstitial damage. These mesangial matrices were stained markedly by antisera for collagen type IV and by fibronectin, but not by collagen type I. Localization of TGF-beta protein was also detected in the mesangium of the HIGA mice. The positive mesangial IgA deposition was maintained consistently by this mating procedure and became more marked with age. Size analysis of IgA from ten pooled HIGA mice aged 50 to 60 weeks revealed dominant polymeric IgA in sera and dimeric IgA in glomerular eluates. Clonal analysis of serum IgA disclosed heterogeneous spectrotypes in a wide pH range (4.5 to 6.5), in contrast to very limited spectrotypes in the acidic pH range (4.5 to 5.2) of IgA in the glomerular eluates from these mice. The analyses of retroviral gp70 antigen involvement in the HIGA mice disclosed a significant increase of serum levels of gp70 anti-gp70 immune complexes with age, with no relationship to the severity of glomerular gp70 deposition. Northern blot analysis of renal tissue revealed markedly high mRNA expression of collagen type I, IV, fibronectin and TGF-beta even in 10-week-old HIGA mice in comparison with BALB/c mice. The expression became more significant in 60-week-old animals. The genetic background required to induce the expansion of IgA-producing B-cell clones is suggested to be closely related to the increased gene expression of TGF-beta, which induces enhanced glomerular extracellular matrix (especially fibronectin) accumulation in HIGA mice, being possibly mediated by the mesangial deposition of dimeric and highly acidic IgA. This newly established strain may provide a model for investigating the relationship between progressive glomerular sclerotic lesions and the induction of pathogenic IgA in human IgA nephropathy.     

Clinicopathological significance of intratubular giant macrophages in progressive glomerulonephritis

Very large macrophages, which we have termed "giant macrophages" (G-M phi), have been found in renal tubules, some containing cytoplasmic vacuoles. To elucidate their pathophysiological roles, we examined renal biopsy tissues from various primary glomerulonephritis (GN) and tubulointerstitial nephritis (TIN) using immunohistochemistry with monoclonal antibodies against M phi and other cell surface markers. Giant macrophages were absent or rare in TIN, minimal change nephrotic syndrome, and minor glomerular abnormalities, but G-M phi was plentiful in progressive glomerulonephrides such as IgA nephropathy with crescents, membranoproliferative GN, focal segmental glomerulosclerosis, and especially in crescentic GN. These G-M phi were usually seen in the lumen of renal tubules, but occasionally were found in the Bowman's spaces and glomerular tufts, and similar cells were also found in urine. Moreover, they frequently made contact with tubular epithelial cells expressing intercellular adhesion molecule-1, and the tubular epithelial cells in such lesions often had degenerative changes. Giant M phi may damage tubular epithelial cells from the luminal side. Phenotypically, G-M phi showed activated (CD71+) and mature (25F9+) characteristics along with features of M phi (CD68+), and the cytoplasm contained a great deal of lipids. The numbers of G-M phi in renal tissues closely correlated with the degree of hematuria (rho = 0.5, P < 0.001), serum creatinine value (r = 0.63, P < 0.001) in GN patients (N = 96) and with proteinuria in IgA nephropathy patients (r = 0.89, P < 0.001, N = 27). These data suggest that G-M phi are M phi that were activated and matured in certain active inflammatory sites, which flowed into tubules and then into urine. Thus, the existence of G-M phi in biopsy tissue or urine reflect the activity of GN and may have a predictive value for the progression of GN.     

Human malignant thyroid tumors displayed reduced levels of transforming growth factor beta receptor type II messenger RNA and protein

Transforming growth factor beta (TGF-beta) is a physiological regulator of thyroid epithelial cell growth and differentiation. This factor signals through a heteromeric complex composed of type I (TGF-beta receptor type I) and type II [TGF-beta receptor type II (TbetaRII)] receptors. Loss of TbetaRII expression has been related to resistance to TGF-beta inhibition of cell proliferation. In the present work, we analyzed the TbetaRII expression in a series of human thyroid tumors, from benign lesions (adenomas) to neoplastic lesions of increasing aggressiveness (papillary and follicular carcinomas) up to the extremely aggressive anaplastic tumors. Results obtained indicated a clear reduced expression of TbetaRII mRNA only in the group of thyroid carcinomas when compared with their relative normal tissues. Immunohistochemical analyses with specific anti-TbetaRII antibodies confirm these observations. These data indicate that loss of expression of TbetaRII can contribute to thyroid cancer progression, inducing cancer cells to escape the growth-inhibitory effect of TGF-beta.     

Detection of urinary interleukin-8 in glomerular diseases

To clarify the mechanism of neutrophil infiltration in glomerulonephritis, both urinary and plasma levels of a potent neutrophil chemotactic cytokine, interleukin-8 (IL-8), were measured in 40 healthy volunteers and 96 patients with various renal diseases. The plasma IL-8 levels were less than 16 pg/ml. The urinary IL-8 levels were elevated in several renal diseases including IgA nephropathy (17 of 43), acute glomerulonephritis (4 of 6), lupus nephritis (11 of 15), purpura nephritis (2 of 4), membranoproliferative glomerulonephritis (1 of 1), and cryoglobulinemia (2 of 2). IL-8 was detected immunohistochemically in diseased glomeruli, suggesting its local production. Elevated urinary IL-8 levels during the acute phase or exacerbations were found to be decreased during spontaneous or steroid pulse therapy-induced convalescence in all patients examined. The urinary IL-8 levels were higher in patients with glomerular leukocyte infiltration than in those without infiltration. Collectively, local production of IL-8 in diseased glomeruli might be involved in the pathogenesis of the glomerular diseases and measurement of IL-8 in the urine might be useful for monitoring the glomerular diseases.     

Candida endocrinopathy syndrome with membranoproliferative glomerulonephritis: demonstration of glomerular candida antigen

A boy who had the Candida endocrinopathy syndrome, consisting of mucocutaneous candidiasis, hypoparathyroidism and hypoadrenocorticism, also had hypocomplementemic membranoproliferative glomerulonephritis. A renal biopsy at age 16 showed lobular glomerulonephritis with chronic interstitial inflammation. Glomerular and focal tubular deposition of IgG and C3, but not C4, were seen by immunofluorescence microscopy. Electron microscopy revealed dense intramembranous deposits in glomerular, tubular and Bowman's capsul basement membranes. C. albicans antigenic material was detected in the glomeruli by immunofluorescence microscopy using an FITC-labelled rabbit antiserum to the patient's organism. These fidings suggest that chronic C. albicans infection led to an immune complex form of nephritis. Clinical and laboratory evidence of resolution of his nephritis and return to normal serum levels of C3 followed prolonged antifungal therapy.     

Contractile cells of the kidney in primary glomerular disorders: an immunohistochemical study using an anti-alpha-smooth muscle actin monoclonal antibody

Mesangial cells of the renal glomerulus are thought to have contractile properties, resembling those of smooth muscle cells. Since actin synthesis in mesangial cells is increased in selected animal models of glomerulonephritis, we evaluated the expression of alpha-smooth muscle actin (ASMA), the principal actin isoform found in smooth muscle cells, in biopsy specimens from patients with primary glomerular disorders and in control tissues. Normal glomeruli and glomeruli in acute tubulointerstitial disorders showed few or no ASMA-positive cells in the glomeruli. In contrast, ASMA expression in mesangial cells was increased in minimal change disease, focal segmental glomerulosclerosis, mesangial proliferative glomerulonephritis, membranous glomerulonephritis, and immunoglobulin A nephropathy. In membranoproliferative glomerulonephritis and cryoglobulinemic glomerulonephritis both mesangial and capillary loop ASMA-positive cells were observed with a segmental distribution. In addition, ASMA-positive interstitial cells were seen in many biopsy specimens and often were increased in number in biopsy specimens showing early interstitial fibrosis and tubular atrophy. We conclude that ASMA synthesis in mesangial cells is upregulated in a variety of glomerular disorders, frequently associated with increased cell proliferation and mesangial matrix production. This phenotypic change may be an indicator of mesangial cell activation after injury and may have important pathophysiologic consequences.     

Nephritis in systemic lupus erythematosus in children

Twenty-five patients, aged six to 18 years, with lupus nephritis, followed for two to 103 months (median 22 months), have been classified according to renal histology into groups with diffuse proliferative glomerulonephritis (18), focal proliferative nephritis (2), and membranous nephropathy (5). Correlations have been made among specific histologic groups, clinical findings, renal function studies, urinary findings, and response to therapy. In sequential renal biopsies, lesions progressed in most patients with diffuse proliferative and membranous changes; however, chronic renal failure occurred in only one patient and the five-year survival rate (60.9%) is better than previously reported in pediatric patients.     

Occurrence of anti-C1q antibodies in IgA nephropathy

BACKGROUND: The pathogenic mechanisms and the antigens involved in the establishment and progress of IgA nephropathy are unknown. As antibodies against C1q have been reported to correlate with SLE nephritis, we analysed the occurrence of these antibodies in IgA nephropathy in order to investigate the possibility of pathogenetic similarities in these renal disorders. METHODS: The occurrence of IgA- and IgG anti-C1q antibodies (anti-C1q) were determined by ELISA in patients with IgA nephropathy (n = 36) and SLE nephritis (n = 37), diseases both known to be associated with circulating immune complexes. Levels of these antibodies were also determined in two other glomerular diseases, i.e. idiopathic membranous glomerulonephritis (n = 7) and minimal change disease (n = 2), in which circulating immune complexes are usually not present, and in 40 healthy controls. RESULTS: IgA anti-C1q was observed in increased titres in 11/36 of the patients with IgA nephropathy, in 2/37 of the patients with SLE nephritis (both with proliferative disease) and in 1/9 of the patients with membranous and minimal change disease (P < 0.001). Increased titres of IgG anti-C1q were observed in 1/36 of the patients with IgA nephropathy, in 17/37 of the patients with SLE nephritis and in 0/9 of the patients with membranous and minimal change disease (P < 0.001). There were no correlations between the levels of anti-C1q antibodies and clinical parameters such as degree of proteinuria, haematuria, or renal function. Nor was there any correlation to the concentration of C3a and the terminal complement complex (TCC) in patients with IgA nephropathy. CONCLUSIONS: The occurrence of anti-C1q antibodies in both IgA nephropathy and SLE nephritis, albeit of different predominating isotypes, indicates the possibility of a similar pathogenic mechanism involved in these renal disorders. The occurrence of IgA anti-C1q antibodies in patients with IgA nephropathy has to our knowledge not previously been reported.     

Long-term observation of glomerulonephritis induced by multiple injections with anti-Thy-1 antibody in rats

Multiple injections with a mouse monoclonal anti-rat Thy-1 antibody (five times, at weekly intervals) induced marked glomerular sclerotic lesions which are characterized by adhesion of glomerular capillaries to Bowman's capsule and persistent proteinuria in rats. Abnormal production of type I collagen and increased accumulation of type IV collagen and fibronectin were observed in these glomeruli. The glomerular expression of mRNA for these matrix components and transforming growth factor-beta1 (TGF-beta1) were markedly increased at 4 days after the last injections with anti-Thy-1 antibody, but decreased to below the levels of control rats at 5 weeks. This may be down-regulation of mRNA in mesangial cells. The glomerular sclerotic lesions were not progressive but the process of glomerular healing seemed to be retarded. The proteinuria and the glomerular adhesion were irreversible.     

Pathogenesis of IgA nephropathy: role of outer membranes of Haemophilus parainfluenzae antigens

IgA nephropathy is characterized by IgA deposits, predominantly in the glomerular mesangium and mesangial proliferative glomerulonephritis. Concerning its pathogenesis, several investigators suggest that the deposited IgA is an antibody to viral, bacterial, or dietary antigens. Such reports strengthen the possibility of a relationship between mucosal immunity and the pathogenesis of IgA nephropathy. We previously observed that Haemophilus parainfluenzae (HP) is more commonly isolated from the pharynx of patients with IgA nephropathy than from those with other diseases. We have also identified the glomerular deposition of the outer membranes of HP antigens (OMHP) and an increased serum concentration of IgA antibodies against OMHP in patients with IgA nephropathy. These findings suggest that HP has a role in the etiology of IgA nephropathy.     

Tubular up-regulation of clusterin mRNA in murine lupus-like nephritis

Clusterin, a widely distributed glycoprotein, is detected in most tissues and in numerous physiological fluids. In the kidney, this protein is constitutively expressed in tubular epithelial cells, and its expression is enhanced following tubular injuries. In addition, clusterin has been detected in glomerular immune deposits of glomerulonephritis. The present study was designed to define the sites of clusterin mRNA accumulation in murine lupus-like nephritis in comparison with murine tubulopathies. In lupus-like nephritis, a significant increase of clusterin mRNA abundance was demonstrated. This up-regulation was localized exclusively in tubular epithelial cells exhibiting tubulointerstitial alterations, whereas no clusterin mRNA was detectable in diseased glomeruli, excluding an active synthesis of clusterin by glomerular cells. A similar tubular increase of clusterin mRNA abundance was observed in myeloma-like cast nephropathy induced by IgG3 monoclonal cryoglobulins and even in the absence of any detectable histological alterations in a model of septic shock induced by the injection of bacterial lipopolysaccharides. Our results suggest that tubular epithelial cells are the only sites of clusterin mRNA accumulation during the course of lupus-like nephritis and that the tubular up-regulation of clusterin gene expression may reflect the cellular response to various types of tubular injuries.     

Statistical methods for dependent competing risks

In this study, the kinetics of glomerular endothelial cells during the repair process following glomerular injury was investigated in a model of mesangial proliferative glomerulonephritis induced by Habu-snake venom (HSV) in rats. Intravenous injection of HSV led to a cystic ballooning type lesion at day 1. Subsequently a marked segmental proliferative lesion was observed in the cystic areas at day 5. Thereafter cellularity decreased and reconstruction of the glomerular tuft was gradually observed with time. The histological structure of the glomeruli had almost returned to normal 21 days following HSV injection. After prominent depletion at day 1, the number of endothelial cells increased rapidly and reached a plateau at day 7, not significantly different from that of the control group. Morphologically endothelial cell elongation from the vascular pole into the cystic lesion was seen together with premature capillary formation in the proliferative lesion. Accompanying the reduction of mesangial expansion, the endothelial cells gradually formed definite capillary lumens. We conclude that the mesangial proliferative glomerulonephritis induced by HSV recovers to its original structural state and that the migration and proliferation of endothelial cells with accompanying capillary formation are essential for the repair process, in addition to mesangial cell proliferation.     

Comparative clinical and biochemical analyses of two methods of pancreatic cannulation in pigs

Over the last 16 years the evolution of 24 pregnancies in 17 women with biopsy-proven glomerular disease was analyzed. The underlying renal histology was IgA nephropathy in 8 cases, lupus nephritis in 7, mesangiocapillary glomerulonephritis type I in 1, and focal segmental glomerulosclerosis in 1. All but 2 had normal renal function before conception and 3 were hypertensive. Fetal survival rate was 75%. There were 6 preterm deliveries (33.3%), 3 newborns small for gestational age (17%), 1 stillbirth, and 5 therapeutic abortions. The perinatal mortality was 5.5%. De novo hypertension occurred in 8 pregnancies (33.3%). In 11 pregnancies (46%) increased proteinuria was diagnosed and in 6 (25%) a decline in maternal renal function was recorded. Permanent impairment of renal function was seen in 2 women with renal insufficiency before conception. Maternal hypertension and renal function impairment were associated more frequently with obstetric complications. In conclusion, pregnancy is safe for normotensive mothers with glomerular diseases and normal renal function. Hypertension and impaired renal function at conception seem to carry increased risk for mothers and fetuses. Low-dose immunosuppressive treatment during pregnancy is not harmful for the fetus.     

SPARC is expressed by mesangial cells in experimental mesangial proliferative nephritis and inhibits platelet-derived-growth-factor-medicated mesangial cell proliferation in vitro

Mesangial cell proliferation is a characteristic feature of many glomerular diseases and often precedes extracellular matrix expansion and glomerulosclerosis. This study provides the first evidence that SPARC (secreted protein acidic and rich in cysteine) could be an endogenous factor mediating resolution of experimental mesangial proliferative nephritis in the rat. SPARC is a platelet-derived-growth-factor-binding glycoprotein that inhibits proliferation of endothelial cells and fibroblasts. We now show that SPARC is synthesized by mesangial cells in culture and that SPARC mRNA levels are increased by platelet-derived growth factor and basic fibroblast growth factor. Recombinant SPARC or the synthetic SPARC peptide 2.1 inhibited platelet-derived-growth-factor-induced mesangial cell DNA synthesis in vitro. In a model of experimental mesangioproliferative glomerulonephritis, SPARC mRNA was increased 5-fold by day 7 and was identified in the mesangium by in situ hybridization. Similarly, SPARC was increased in glomerular mesangial cells and visceral epithelial cells by day 5 and reached maximal expression levels by day 7. Mesangial cell proliferation increased by 36-fold on day 5 and decreased abruptly on day 7. Maximal expression of SPARC was correlated with the resolution of mesangial cell proliferation. We propose that SPARC functions in part as an endogenous inhibitor of platelet-derived-growth-factor-mediated mesangial cell proliferation in glomerulonephritis and that it could account for the resolution of cellular proliferation in this disease.     

On the incidence of renal vein thrombosis in the nephrotic syndrome

Forty-eight patients with nephrotic syndrome were evaluated prospectively; the studies included inferior venacavagrams and ventilation perfusion lung scans. Eleven patients were found to have renal vein thrombosis (RVT). Eight of 21 patients with membranous glomerulonephritis (MGN) or membranoproliferative glomerulonephritis (MPGN) has RVT (38%). Clinical, laboratory, and pathological findings were not different among those patients with MGN and MPGN whether RVT was present or not. Patients with diabetic nephropathy or lupus nephritis did not have RVT. There was a high incidence of other thromboembolic phenomena as well as asymptomatic perfusion defects demonstrated by the lung scan, especially in patients with MGN or MPGN. These data suggest the disease process underlying the nephrotic syndrome may play a paramount role in the genesis of RVT or thromboembolic phenomena.