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.

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.

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.

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.

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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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.

[Chlamydia pneumoniae persistent infection is associated with primary IgA nephropathy].

OBJECTIVE: To explore the correlations between Chlamydia pneumoniae (CP) infection and IgA nephropathy (IgAN). METHODS: Seventy patients with primary IgAN were enrolled in the study. Seventy serum specimens from healthy blood donors and twelve renal autopsy specimens from accidental death bodies were regarded as control groups. Serum CP IgG and CP IgA antibody titers were detected by indirect immunofluorescence. CP DNA of renal tissue was measured by fluorescent quantitative PCR. Finally, using statistical methods, we analyzed the correlations of CP infection and CP DNA of renal tissue with clinical manifestations and kidney pathological changes of IgAN patients. RESULTS: The rate of CP persistent infection in IgAN group was higher than that of healthy blood donor group (P<0.01). The rate was not significantly different within the IgAN group, such as among acute infection, previous infection and no infection subgroups (P>0.05). It was higher in the patients with gross proteinuria and/or durative renal insufficiency than in non-gross proteinuria patients (P<0.05). The scores of glomerular patholopical and tubulointerstitial injury of CP persistent infection patients were higher than those of non-persistent infection ones (P<0.05). The renal injury of CP persistent infection patients was more severe than that of non-persistent infection ones. The positive rate of CP DNA in gross proteinuria and/or renal insufficiency patients was higher than that of non-gross proteinuria patients (P<0.05). The scores of glomerular pathological and tubulointerstitial injury of positive CP DNA patients were respectively higher than those of negative CP DNA ones (P<0.05, P<0.01). The renal injury of patients with positive CP DNA was more severe than that of negative CP DNA ones. CP persistent infection was obviously correlated with renal CP DNA (P<0.01). CONCLUSION: Primary IgAN is associated with CP persistent infection, but not with CP previous infection or CP acute infection.

Acute post-streptococcal glomerulonephritis with acute kidney injury in nephrotic syndrome with the glomerular deposition of nephritis-associated plasmin receptor antigen.

We herein report the case of a 17-year-old man who developed an increased plasma creatinine level (11.1 mg/dL) and oliguria with massive proteinuria (27.3 g/day) four weeks after an abraded wound to his right knee. The histology of the renal biopsy specimens showed diffuse endocapillary proliferative glomerulonephritis with the deposition of nephritis-associated plasmin receptor in the glomerulus. A case of acute kidney injury due to nephrotic syndrome caused by acute post-streptococcal glomerulonephritis was diagnosed. His renal function and proteinuria were improved with supportive care, including hemodialysis, without the administration of immunosuppressive agents.

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.

The association of polymorphonuclears with humps in acute postinfectious glomerulonephritis.

It is currently considered that hump dense deposits developed during an acute poststreptococcal glomerulonephritis become finally dissolute by three hypothetical mechanisms: loosing their electron density, internalization and processing by podocytes and by incorporation in the glomerular basal lamina (GBM). Analyzing ultrastructurally the association of polymorphonuclear leukocytes and hump deposits, we emphasized features endorsing the hypothesis that the immune complexes of dense deposits are discharged in the circulation under the leukocytes activity. The active polymorphonuclear cells are melting the GBM in the area of contact by complement activation and by the NAPlr bound plasmin. The reversed flow of immune complexes from humps towards the blood circulation leaves fading, wrinkled shaped humps, before total dissolution.

IgA nephropathy associated with pleuropulmonary tuberculosis.

A 34-year-old man presented with polymerase chain reaction-positive pleuropulmonary tuberculosis with asymptomatic subnephrotic proteinuria and microscopic haematuria. He was diagnosed to have IgA nephropathy on renal biopsy. The patient was started on a four-drug anti-tuberculous therapy. Healing of the pleuropulmonary lesions along with disappearance of proteinuria and haematuria were seen both at one month and six months post-treatment, with no relapse of renal symptoms at one-year follow-up.

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.

CXCL1/KC and CXCL2/MIP-2 are critical effectors and potential targets for therapy of Escherichia coli O157:H7-associated renal inflammation.

Neutrophilia is a characteristic of hemolytic uremic syndrome caused by Shiga toxin (Stx2)-producing Escherichia coli. However, the role of neutrophils in the toxin-induced renal injury occurring in enterohemorrhagic E. coli infection remains undefined. We report the trafficking of neutrophils to the kidney of C57BL/6 mice throughout a 72-hour time course after challenge with purified E. coli Stx2 and lipopolysaccharide (LPS). Increased neutrophils were observed in the renal cortex, particularly within the glomeruli where a more than fourfold increase in neutrophils was noted within 2 hours after challenge. Using microarray analysis, an increased number of transcripts for chemoattractants CXCL1/KC (69-fold at 2 hours) and CXCL2/MIP-2 (29-fold at 2 hours) were detected. Ribonuclease protection assays, Northern blotting, enzyme-linked immunosorbent assay, and immunohistochemistry confirmed microarray results, showing that both chemokines were expressed only on the immediate periglomerular epithelium and that these events coincided with neutrophil invasion of glomeruli. Co-administration of Stx2 with LPS enhanced and prolonged the KC and MIP-2 host response (RNA and protein) induced by LPS alone. Immunoneutralization in vivo of CXCL1/KC and CXCL2/MIP-2 abrogated neutrophil migration into glomeruli by 85%. These data define the molecular basis for neutrophil migration into the kidney after exposure to virulence factors of Shiga toxin-producing E. coli O157:H7.

LipL46 is a novel surface-exposed lipoprotein expressed during leptospiral dissemination in the mammalian host.

Leptospirosis is a widespread zoonosis caused by invasive spirochaetes belonging to the genus Leptospira. Pathogenic leptospires disseminate via the bloodstream to colonize the renal tubules of reservoir hosts. Little is known about leptospiral outer-membrane proteins expressed during the dissemination stage of infection. In this study, a novel surface-exposed lipoprotein is described; it has been designated LipL46 to distinguish it from a previously described 31 kDa peripheral membrane protein, P31(LipL45), which is exported as a 45 kDa probable lipoprotein. The lipL46 gene encodes a 412 aa polypeptide with a 21 aa signal peptide. Lipid modification of cysteine at the lipoprotein signal peptidase cleavage site FSISC is supported by the finding that Leptospira interrogans intrinsically labels LipL46 during incubation in medium containing [(14)C]palmitate. LipL46 appears to be exported to the leptospiral outer membrane as a 46 kDa lipoprotein, based on Triton X-114 solubilization and phase partitioning studies, which included the outer and inner membrane controls LipL32 and LipL31, respectively. Surface immunoprecipitation and whole-cell ELISA experiments indicate that LipL46 is exposed on the leptospiral surface. Immunohistochemistry studies demonstrated expression of LipL46 by leptospires found in the bloodstream of acutely infected hamsters. Leptospires expressing LipL46 were also found in the intercellular spaces of the liver, within splenic phagocytes, and invading the glomerular hilum of the kidney. Infection-associated expression is supported by the finding that LipL46 is a major antigen recognized by sera from infected hamsters. These findings indicate that LipL46 may be important in leptospiral dissemination, and that it may serve as a useful serodiagnostic antigen.

Induction of glomerular alkaline phosphatase after challenge with lipopolysaccharide.

Alkaline phosphatase (AP) can be considered as a host defence molecule since this enzyme is able to detoxify bacterial endotoxin at physiological pH. The question emerged whether this anti-endotoxin principle is inducible in the glomerulus and if so, which glomerular cells might be involved in the expression of ectoAP after stimulation with pro-inflammatory agents. Therefore kidneys of rats treated with either lipopolysaccharide (LPS), E. coli bacteria or non-toxic monophosphoryl lipid A (MPLA) were examined for AP activity 6 or 24 h after challenge. In addition cultures of endothelial cells or mesangial cells were evaluated for AP activity after stimulation with either LPS, TNFalpha or IL-6, and mRNA for AP was studied in TNFalpha-stimulated and control mesangial cells. The results show significant up-regulation of glomerular AP in LPS- or E. coli-injected rats compared to rats injected with MPLA. Endothelial and mesangial cells in vitro showed significant up-regulation of AP activity following stimulation with LPS, TNFalpha or IL-6, whereas increased mRNA for AP was observed in mesangial cells after TNFalpha stimulation compared to non-stimulated control cells. Since it appeared that hydrolysis occurred when endotoxin was used as a substrate in the histochemical staining, we concluded that inducible glomerular ectoAP may reflect a local endotoxin detoxifying principle of the kidney.

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.

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.