Autoimmunity in Acute Poststreptococcal GN: A Neglected Aspect of the Disease.

Acute poststreptococcal GN (APSGN) is the prototype of immune complex GN and is associated with manifestations of autoimmune reactivity that have been neglected as epiphenomena. Recently, studies have demonstrated transient antifactor B autoantibodies that activate the alternative complement pathway, bringing self-immunity to a central position in the pathogenesis of APSGN. Therefore, examining other manifestations of autoimmunity that have been reported in association with poststreptococcal GN is of interest. This article reviews the renal and extrarenal manifestations of autoimmune reactivity in APSGN and considers their potential relevance in modifying the usually benign clinical course of the disease. It also discusses related aspects of the nephritogenic antigens, complement activation, and genetic elements associated with immune reactivity and their potential relevance to the familial incidence of the disease.

Disseminated Mycobacterium bovis infection post-kidney transplant following remote intravesical BCG therapy for bladder cancer.

Intravesical Bacillus Camlette-Guérin (BCG) is the treatment of choice for non-muscle invasive bladder cancer, and has been used successfully for over 40 years. A rare and potentially fatal complication of intravesical BCG therapy is BCG-induced sepsis. We report a rare case in which a patient with end-stage renal disease secondary to chronic granulomatous interstitial nephritis underwent remote, pre-transplant intravesical BCG treatment for high-grade non-invasive papillary bladder carcinoma. The patient subsequently received a deceased donor kidney transplant 5 years after BCG therapy, with thymoglobulin induction therapy and standard triple maintenance immunosuppression. Two years post-transplant, he developed BCG-induced sepsis confirmed by cultures from urine, blood, and left native kidney biopsy. He died from disseminated BCG-induced sepsis and failure of his renal allograft. This case highlights the potential adverse reactions associated with intravesical BCG therapy that may occur years after bladder cancer therapy is completed, and should heighten physician awareness for BCG-related infections during pre-transplant assessment and post-transplant care of solid organ transplants recipients.

Nephritis-associated plasmin receptor (NAPlr) positive glomerulonephritis caused by Aggregatibacter actinomycetemcomitans bacteremia: A case report.

Infection-related glomerulonephritis (IRGN) develops after various infections. It was previously thought to be caused by Streptococcus species alone but can also be caused by other pathogens. Nephritis-associated plasmin receptor (NAPlr) was discovered as a candidate nephritis-inducing factor in acute post-streptococcal glomerulonephritis. More recently, renal lesions caused by other pathogens were found to be positive for the same molecular marker. We report the case of a 64-year-old man who experienced repeated fever for several months and presented with progressively-deteriorating renal function. He had previously undergone aortic valve replacement. Aggregatibacter actinomycetemcomitans, a component of the oral flora, was detected in a blood culture. Renal biopsy showed diffuse proliferative glomerulonephritis. Immunofluorescence staining of the kidney specimen was positive for immunoglobulins, complements, and NAPlr. The patient was diagnosed with infectious endocarditis and IRGN. Six weeks of intravenous antibiotic therapy improved the patient's clinical condition and kidney function. In this case, IRGN was caused by a rare pathogen. This is the first published case to show NAPlr positivity in the glomeruli after systemic infection with the periodontal bacteria, Aggregatibacter actinomycetemcomitans. This case and subsequent research might expand the concept of IRGN, anchored by NAPlr as a key diagnostic biomarker.
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The role of nephritis-associated plasmin receptor (NAPlr) in glomerulonephritis associated with streptococcal infection.

It is well known that glomerulonephritis can occur after streptococcal infection, which is classically referred to as acute poststreptococcal glomerulonephritis (APSGN). The pathogenic mechanism of APSGN has been described by so-called immune complex theory, which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexes in situ and/or the deposition of circulating antigen-antibody complexes. However, the exact entity of the causative antigen has remained a matter of debate. We isolated a nephritogenic antigen for APSGN from the cytoplasmic fractions of group A streptococcus (GAS) depending on the affinity for IgG of APSGN patients. The amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen) receptor of GAS. Thus, we termed this antigen nephritis-associated plasmin receptor (NAPlr). Immunofluorescence staining of the renal biopsy tissues with anti-NAPlr antibody revealed glomerular NAPlr deposition in essentially all patients with early-phase APSGN. Furthermore, glomerular plasmin activity was detected by in situ zymography in the distribution almost identical to NAPlr deposition in renal biopsy tissues of APSGN patients. These data suggest that NAPlr has a direct, nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of APSGN by maintaining plasmin activity.

Differentiating Staphylococcus infection-associated glomerulonephritis and primary IgA nephropathy: a mass spectrometry-based exploratory study.

Staphylococcus infection-associated glomerulonephritis (SAGN) and primary IgA nephropathy (IgAN) are separate disease entities requiring different treatment approaches. However, overlapping histologic features may cause a diagnostic dilemma. An exploratory proteomic study to identify potential distinguishing biomarkers was performed on formalin fixed paraffin embedded kidney biopsy tissue, using mass spectrometry (HPLC-MS/MS) (n = 27) and immunohistochemistry (IHC) (n = 64), on four main diagnostic groups-SAGN, primary IgAN, acute tubular necrosis (ATN) and normal kidney (baseline transplant biopsies). Spectral counts modeled as a negative binomial distribution were used for statistical comparisons and in silico pathway analysis. Analysis of variance techniques were used to compare groups and the ROC curve to evaluate classification algorithms. The glomerular proteomes of SAGN and IgAN showed remarkable similarities, except for significantly higher levels of monocyte/macrophage proteins in SAGN-mainly lysozyme and S100A9. This finding was confirmed by IHC. In contrast, the tubulointerstitial proteomes were markedly different in IgAN and SAGN, with a lower abundance of metabolic pathway proteins and a higher abundance of extracellular matrix proteins in SAGN. The stress protein transglutaminase-2 (TGM2) was also significantly higher in SAGN. IHC of differentially-expressed glomerular and tubulointerstitial proteins can be used to help discriminate between SAGN and IgAN in ambiguous cases.

Antigenic streptococcal components in acute glomerulonephritis.

Fluorescein-labeled immunoglobulin G fractions from serums of patients with acute glomerulonephritis and from many normal serums stained the glomerular basement membrane and mesangium of renal tissue from patients with early acute glomerulonephritis; these serums did not stain the corresponding tissues from patients with any other kidney disease. Previous absorption of the serum fraction with frozen and thawed nephritogenic beta hemolytic streptococci abolished all staining. Other bacteria studied did not abolish the staining. Only the plasma membrane of the streptococcus absorbed the immunoglobulin G fraction; such absorption eliminated staining. Fluorescein-labeled antiserums against streptococcal plasma membrane had staining properties similar to patients' serums.

Mycotic encephalitis and nephritis in a dog due to infection with Cladosporium cladosporioides.

The dematiaceous fungus Cladosporium cladosporioides is a widely distributed saprophyte that is reported to occasionally infect the lung, skin, eye and brain of humans. This report describes a German shepherd dog with granulomatous encephalitis and nephritis due to C. cladosporioides infection. Although the fungal organisms appeared non-pigmented in haematoxylin and eosin stained sections, they were readily identified with histochemical stains. Semi-nested polymerase chain reaction using universal fungal primers amplified fungal DNA from fixed tissue that had identity to that of C. cladosporioides on sequencing.

Association of brucellosis with renal tubular and glomerular damage in children in Turkey.

Brucellosis is a multisystem disease that may present with a broad spectrum of clinical manifestations. Until now, no studies have been performed on renal tubular disorders in patients with brucellosis. The present study aims to investigate renal tubular disorders in patients with brucellosis. This prospective case-control study includes a total of 31 brucellosis patients (Group 1) and 30 healthy controls (Group 2) matched for age and sex. Renal tubular functions of children who were diagnosed as having brucellosis in outpatient pediatric clinics were evaluated. First-morning urine samples were collected from Group 1 and Group 2 at the same time. Urea, creatinine, potassium, sodium, and phosphorus were determined in serum and urine by an autoanalyzer. Tubular reabsorption and excretion of urine electrolytes were calculated using the related formulas. Patients with brucellosis had significantly lower levels of tubular reabsorption of phosphorus and serum phosphorus than those of the control group. Furthermore, urine sodium and serum potassium levels and fractionated sodium excretion of brucellosis patients were significantly higher than healthy control group. Estimated glomerular filtration rate was remarkably higher in the patient group (P < 0.001).We concluded that tubular and glomerular functional parameters demonstrate deterioration in patients with brucellosis compared to those in healthy participants.

Streptococcal Infection-related Nephritis (SIRN) Manifesting Membranoproliferative Glomerulonephritis Type I.

We herein report the case of an 18-year-old boy who developed nephrotic syndrome and hypertension after upper airway inflammation. Post-streptococcal acute glomerulonephritis was diagnosed on the basis of a high antistreptolysin O titer, hypocomplementemia, proteinuria, and microscopic hematuria. A renal biopsy was performed due to persistent proteinuria, and the pathological diagnosis was membranoproliferative glomerulonephritis (MPGN) type I. Glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr), a nephritogenic group A streptococcal antigen, and plasmin activity was found in a similar distribution as NAPlr deposition. This rare case of streptococcal infection-related nephritis (SIRN) manifesting MPGN type I supports the histological diversity of SIRN.

Glycolipid receptors for verotoxin and Helicobacter pylori: role in pathology.

Eukaryotic cell surface glycolipids can act as both the primary interface between bacteria and their host and secondly as a targeting mechanism for bacterial virulence factors. The former is characterized by redundancy in adhesin-receptor interactions and the latter by a higher affinity, more restrictive glycolipid binding specificity for targeting. Interactions of verotoxin with its glycolipid receptor globotriaosylceramide and Helicobacter pylori binding to a variety of different glycolipids, which can be environmentally regulated, provide examples of these differing modes of glycolipid receptor function. Verotoxins are involved in endothelial targeting in the microangiopathies of hemorrhagic colitis and hemolytic uremic syndrome (HUS). The highly restricted binding specificity and crystal structure of the verotoxin B subunit have allowed theoretical modeling of the Gb3 binding site of the verotoxin B subunit pentamer which provides an approach to intervention. Studies of the role of glycolipid function in verotoxin-induced disease have concentrated on the distribution of Gb3 and its ability to mediate the internalization of the toxin within the target cell. The distribution of Gb3 within the renal glomerulus plays a central role in defining the age-related etiology of HUS following gastrointestinal infection with VT producing Escherichia coli. H. pylori, on the other hand, instigates a less distinct but more complex disseminated gastric inflammation. Studies on the role of glycolipid receptors in H. pylori infection have been bogged down in establishing the importance of each binding specificity defined. In addition, the physiological condition of the organism within the various binding assays has not been extensively considered, such that spurious non-physiological interactions may have been elucidated. The identification and cloning of a Le(b) binding adhesin and the identification of cell surface hsp70 as a mediator of sulfoglycolipid binding under stress conditions may now allow a more molecular approach to define the role of glycolipid recognition in this infection.

Characterization of age-associated kidney disease in Wistar rats.

Kidney disease was studied patho-histologically, electron microscopically and immunologically in Wistar rats ranging in age from 2 weeks to 24 months. Glomerular lesions characterized by adhesion of podocyte foot processes were first detected at 3 months of age. The kidney lesions became more pronounced with age, as manifested by an increase of mesangial matrix, basement membrane thickening, crescent formation and hyalinization of glomeruli, and tubular degeneration. Evidence for the deposition of immune complexes in the kidney was obtained by immunofluorescence and electron microscopy, as well as by immuno-electrophoretic analysis of kidney elutions. Tests with antiserum reagent against Moloney leukemia virus antigen revealed its presence in some but not all glomeruli. The presence of other viruses in Moloney leukemia virus negative glomeruli was not ruled out. Serum autoantibody against an array of rat tissues could not be detected. Therefore, it would appear that autoimmune mechanism may not be the primary underlying cause of pathogenesis of the disease. Accordingly, the disease could be referred to as chronic immune complex glomerulonephropathy with nephrotic syndrome, but sources of the antigens in the complex were mostly unknown, althougn virus could be one portion of them. The possibility that diet antigens may also be present in the complex seems unlikely because attempts to demonstrate serum antibodies against diet pellet in old rats were unsuccessful.

Human cytomegalovirus infection of kidney glomerular visceral epithelial and tubular epithelial cells in culture.

Evidence suggests that human cytomegalovirus is resident in the kidneys of seropositive donors at the time of transplantation, and CMV has been implicated in both glomerulonephritis and interstitial nephritis. In this study we assessed the interactions of CMV with two human renal cell types in culture: glomerular visceral epithelial cells (GVE) and renal tubular epithelial (RTE) cells. GVE permitted viral adsorption, penetration, nuclear translocation, and restricted viral transcription. However, early viral protein expression was not detectable by immunofluorescence and infectious virions were not produced. In contrast, retinoic acid-treated GVE permitted early viral protein expression and supported CMV replication. RTE also permitted viral adsorption and penetration. CMV-specific early proteins were readily observed by immunofluorescence, and CMV DNA replication was observed by DNA dot blot hybridization. Assays comparing viral yield with viral DNA synthesis indicated that RTE were capable of supporting persistent and prolonged viral expression without significant cell death for at least 55 days after infection. We believe that these findings should explain chronic viruria in individuals with symptomatic and asymptomatic CMV infection. In addition, GVE could also be a potential source of CMV transmission when altered by disease or transplantation.

Group A streptococcal antigen in the glomeruli of children with Henoch-Schönlein nephritis.

BACKGROUND: Although the pathogenesis of Henoch-Schönlein nephritis (HSN) remains unclear, there is substantial evidence that it is an immune complex-mediated disease. HSN is preceded by upper-respiratory tract infection in 30% to 50% of patients, but there is no evidence that group A streptococcal (GAS) infection has a pathogenetic role in this disease. Recently, nephritis-associated plasmin receptor (NAPlr), a GAS antigen, was found primarily in the glomerular mesangium of patients with early-stage acute poststreptococcal glomerulonephritis. METHODS: To determine the possible role of NAPlr in HSN, expression of the receptor was determined in glomeruli using fluorescein isothiocyanate-labeled rabbit polyclonal anti-NAPIr antibody, and serum antistreptolysin O (ASO) titers were measured in children with HSN. RESULTS: Ten of 33 patients (30%) with HSN showed segmental or global mesangial staining with NAPlr antibody, whereas only 4 of 120 patients (3%) with other renal diseases were positive (P < 0.001, Fisher's exact test). Patients with HSN also showed significantly greater ASO titers than patients with other renal diseases (P = 0.03, Mann-Whitney U test). Serum ASO titers were significantly greater in patients with HSN with than without glomerular NAPlr antigen (P = 0.03, Mann-Whitney U test). CONCLUSION: These findings suggest that the deposition of NAPlr in the mesangium, induced by GAS infection, may have a role in the pathogenesis of HSN in some patients. Am J Kidney Dis 41:366-370.

Agarose method for the preparation of isolated glomeruli from human renal biopsies.

We present a technique using glomeruli which are removed by dissection from human renal biopsies and processed for transmission electron microscopy (TEM). Firstly, glomeruli are dissected and isolated from the specimen. Secondly, the collected glomeruli are embedded in agarose with a low gelling temperature. Finally, the embedded glomeruli are processed in the same way as whole pieces of tissue using standard methods for TEM. We have successfully prepared several hundred specimens using this simple and reliable technique. Provided that care is taken to prevent mechanical damage to the glomeruli during collection, no severe artifacts are introduced into the tissue. Even a single glomerulus can be isolated and processed in this way.

Frequency of intraendothelial 'virus-like' particles: an electron microscopy study of 376 human renal biopsies.

Intraendothelial ;virus-like' particles were found in all cases requiring a renal biopsy: in 89% of patients with systemic lupus erythematosus (SLE), in 73% of those receiving renal transplants more than one year before, and in 24.5% of all other renal biopsies.

Role of IgA, IgG, and IgM antibodies against Haemophilus parainfluenzae antigens in IgA nephropathy.

We have recently demonstrated glomerular deposition of outer membranes of Haemophilus parainfluenzae (HP) antigens (OMHP) and the presence of IgA antibody against OMHP in patients with IgA nephropathy (IgA-N). In this study, we analyzed IgA-, IgG-, and IgM-classes of antibodies against OMHP, and the relationship between these antibodies and renal lesions in IgA-N. The subjects included 44 patients with IgA-N and 62 patients with outer glomerular diseases (OGD); the latter group consisted of 23 patients with predominantly IgG or IgM deposits and small amounts of IgA in the mesangium (group A), and 39 with IgG or IgM deposits without IgA (group B). IgA, IgG, and IgM antibodies against OMHP in patients sera were detected by enzyme-linked immunosorbent assay (ELISA). Immunoblotting demonstrated that the IgA, IgG, and IgM antibodies against OMHP in the sera of IgA-N patients bound to components of OMHP with molecular weights of 19.5, 30, and 40.5 kD. The amino acid compositions of these three OMHP components were similar to those reported for the outer membrane protein (OMP) P6 precursor, OMP P5, and OMP P2 (porin) of Haemophilus influenzae. Both IgA-N and group A patients, (i.e. those with IgA-related renal disease), demonstrated a significantly higher level of IgA antibodies against OMHP than did group B patients. However, only IgA-N patients revealed a significant correlation between the IgA-antibody titer and degree of glomerular changes. IgA-N patients with macroscopic hematuria or arterio(lo)sclerosis had a significantly higher IgA antibody titer than other IgA-N patients. There was no relationship between renal lesions and IgG or IgM antibody titers in any group. These findings suggest that IgA antibodies against OMHP are significantly increased in patients with IgA-related renal disease compared to those without mesangial IgA deposits and that a significant relationship between these antibodies and renal lesions exists only in patients with IgA-N.

An in situ hybridization study of herpes simplex and Epstein Barr viruses in IgA nephropathy and non-immune glomerulonephritis.

Renal tissues from forty cases of IgA nephropathy, 20 Singapore and 20 British patients, and 38 patients with non-immune glomerulonephritis were studied by in situ hybridization using DNA probes for the herpes simplex virus (HSV) and Epstein Barr virus (EBV). Two Singapore patients with IgA nephropathy showed HSV antigens in the glomerular mesangium, with one of them having EBV coinfection. In the control non-immune glomerulonephritis cases, 4 patients had viral antigens; 2 with EBV, one with EBV and HSV coinfection, and one with HSV alone. The study indicates that in some cases of IgA nephropathy and in non-immune nephropathy there may be coincidental rather than causal persistent infection by the herpes group of viruses.

Murine cytomegalovirus glomerulonephritis: clinical and ultrastructural observations.

This investigation was initiated to study and correlate the clinical and ultrastructural aspects of glomerulonephritis induced in the laboratory mouse by the intraperitoneal injection of a sublethal dose of murine cytomegalovirus. An attempt was made to ascertain the pathogenesis of the glomerular changes and the resultant viremia. Murine cytomegalovirus infection caused an acute transient glomerulonephritis in young female mice of the HA/ICR strain. Mice that survived a sublethal inoculation of homogenized infected gland developed transient proteinuria and excreted tubular casts. The murine cytomegalovirus infection resulted in a glomerular lesion that was selective for the mesangial cell. After entering the mesangial cell by phagocytosis the virus replicated in the nucleus and was excreted into the channel of the mesangial matrix, with extension toward the periphery of the capillary loop and adjacent to the urinary space. Virus particles were rarely found in the glomerulus after the 5th day of infection and chronic renal disease was not observed.

Viral particles associated with malignant catarrhal fever in deer.

Viral particles associated with malignant catarrhal fever in white-tailed deer (Odocoileus virginianus) and axis deer (Asix axis) are described. Morphologically, the virus resembled the togaviruses and was unlike the herpesvirus which causes wildebeest-associated malignant catarrhal fever (snotsiekte).