Staphylococcus Infection-Associated Glomerulonephritis in a Kidney Transplant Patient: Case Report.

BACKGROUND: Staphylococcus infection-associated glomerulonephritis is a rare cause of graft dysfunction in kidney transplant. Suspicion should be high in the setting of elevation of serum creatinine, active urinary sediment, with or without hypocomplementemia, and simultaneous Staphylococcus aureus infection. A kidney biopsy is usually diagnostic. CASE REPORT: A 56-year-old man, who received a kidney transplant in 1998, with basal serum creatinine of 1.2 mg/dL and normal urinary sediment, was admitted to our kidney transplantation unit with graft dysfunction and a urinary tract infection caused by S aureus with septicemia, treated with antibiotics, in the context of recently intensified immunosuppression for a primary immune thrombocytopenia diagnosed 3 weeks earlier. After antibiotic treatment, the patient persisted with graft dysfunction, edema, and hypertension, with a S aureus isolation in the urine culture, active urinary sediment, and low C3. A kidney biopsy was performed, showing diffuse proliferative endocapillary and mesangial glomerulonephritis, with IgA(++) and C3(++) mesangial and endocapillary deposits in immunofluorescence. The patient was treated symptomatically and maintained his regular immunosuppression. At the last follow-up, his serum creatinine value was stable at 2.5 mg/dL. CONCLUSIONS: The onset of a nephritic syndrome with a simultaneous S aureus infection should lead to suspicion of this uncommon entity, confirmed histologically. Despite its association with poor graft survival, our patient's graft survival remained stable.

Renal manifestations in children co-infected with HIV and disseminated tuberculosis.

Many children in Cape Town are co-infected with human immunodeficiency virus (HIV) and tuberculosis (TB). Granulomatous TB interstitial nephritis is a recognized entity. Our objective was to establish if TB plays a role in renal disease in HIV-infected children. We identified children co-infected with TB and HIV from our database and reviewed their biopsies and clinical notes. Since 2002, 12 renal biopsies or postmortem examinations were performed on HIV-infected children at our institution. The clinical scenario and renal biopsies in four cases (median age 73 months, range 24-108 months) were consistent with TB involvement. The mean CD4 count and percentage of these four patients were 508 cells/microl and 23%, respectively. All four patients presented with culture-proven disseminated TB (not yet on treatment) and had nephrotic range proteinuria and hypoalbuminemia. Three of these patients had renal impairment. The prominent features of the renal biopsies were a severe interstitial inflammatory infiltrate and mild to moderate mesangial proliferation. An interstitial granuloma was seen in one patient. With treatment for the TB, the proteinuria resolved and renal function improved in all four patients. Based on these results, we conclude that TB contributes to proteinuric renal disease in HIV-infected children and that the renal disease improves following TB treatment.

[Microbial nucleic acids in the pathogenesis of glomerulonephritis].

Recent advances in the understanding of innate pathogen recognition revealed that nucleic acids have immunomodulatory functions in inflammation. A set of Toll-like pattern-recognition receptors recognize various types of microbial nucleic acids, i.e. double-stranded viral RNA (TLR3), single-stranded viral RNA (TLR7 and TLR8), and viral and bacterial CpG-DNA (TLR9). All of these TLRs are differentially expressed in the healthy and diseased kidney and TLR ligation was shown to initiate and modulate experimental glomerulonephritis. In this review we summarize the arising evidence in this field and discuss new hypotheses for the pathogenesis of kidney diseases that are triggered by infectious organisms.

A case of renal sarcoidosis with complement activation via the lectin pathway.

A 57-year-old woman with pulmonary sarcoidosis was admitted to the hospital because of an elevation of serum creatinine and blood urea nitrogen. On admission, the laboratory data suggested interstitial nephritis without proteinuria and hematuria, whereas a renal biopsy showed granulomatous interstitial nephritis and mild mesangial proliferative glomerulonephritis. Immunoglobulin and C1q deposits were negative, but mannose-binding lectin, C3, C4d, and C5b-9 deposits were marked in the glomerular mesangial areas. The lectin pathway of complement activation may have contributed to the development of glomerular injury in this patient. DNA of Propionibacterium acnes , which is now strongly suspected as the pathogen of sarcoidosis, was detected in the patient's glomerular mesangial cells; tubular epithelial cells, which were involved in granulomatous inflammation; and mononuclear cells in epithelioid granulomas by in situ hybridization. These findings may add new insights to the pathogenesis of renal sarcoidosis, including its relation to infection, because mannose-binding lectin plays a crucial role in the host defense against various pathogens. From this case of renal sarcoidosis, it is hypothesized that P acnes may be involved in pathogenesis of granulomatous interstitial nephritis and that it plays a role in glomerular complement activation via the lectin pathway.

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.

Haemophilus parainfluenzae antigen and antibody in children with IgA nephropathy and Henoch-Schönlein nephritis.

Although the pathogenesis of immunoglobulin A (IgA) nephropathy and Henoch-Schönlein nephritis (HSN) remains uncertain, there is substantial evidence that they are immune complex-mediated diseases. Recently, Haemophilus parainfluenzae antigens were shown in the glomerular mesangium of adult patients with IgA nephropathy, and greater levels of IgA antibody against H parainfluenzae were also shown in the sera of adult patients with IgA nephropathy. The present study was performed to detect H parainfluenzae antigens and antibody against H parainfluenzae in children with IgA nephropathy and HSN. H parainfluenzae antigens in the mesangium were examined by indirect immunofluorescence, and antibody against H parainfluenzae was examined by enzyme-linked immunosorbent assay. Diffuse global staining of the mesangium with rabbit antisera against H parainfluenzae was shown in 10 of the 32 patients (31%) with IgA nephropathy and 12 of the 34 patients (35%) with HSN. Conversely, only 2 of the 47 patients (4%) with other renal diseases showed staining of glomeruli with rabbit antisera against H parainfluenzae (IgA nephropathy versus other renal diseases, P = 0.003; HSN versus other renal diseases, P = 0.0006). Patients with IgA nephropathy and those with HSN showed significantly greater levels of plasma IgA1 antibody against H parainfluenzae than patients with other renal diseases (IgA nephropathy versus other renal diseases, P = 0.008; HSN versus other renal diseases, P = 0.025). These findings suggest that H parainfluenzae has a role in the cause of these two conditions in a subset of patients.

Interaction of lipopolysaccharide with a mammalian lyso-phosphatidate acyltransferase (LPAAT) transfected into E. coli, and effect of lisofylline on LPAAT transfected into mammalian cells.

1. Lipid A and LPS stimulate LPAAT activity (and hence unsaturated PA formation) in RMC membranes and whole cells. 2. This correlates with cell phenotypic and membrane changes associated with small G proteins. 3. Unsaturated PA and Lipid A have similar effects on cells when given exogenously. 4. Human LPAAT-alpha and -beta isoforms were cloned and transfected into E. coli, demonstrating the ability to restore PA synthesis and reduce lyso-PA accumulation in plsC strains (LPAAT deficient mutants), as well as restoring growth at high temperatures. 5. LPAAT transfection into E. coli plsC (JC201) strains results in an increase in LPS content, suggesting stimulation of LPS synthesis. 6. LPAAT transfection into human A549 lung epithelial carcinoma and endothelial ECV304 cells results in increased cytokine mRNA transcription at baseline, and a significant increase in stimulated cytokine mRNA transcription. In addition, LPAAT transfection also results in increased cytokine release in response to IL-1 beta. 7. LSF, which reduces rodent deaths in sepsis models, reduces unsaturated acyl incorporation into PA in monoblastic cell lines, and reduces serum FFA increase in human sepsis, also reduces unsaturated acyl incorporation into PA in ECV304 cells. LPAAT-alpha transfection increases linolenate incorporation into PA at the expense of linoleate incorporation, which is reversed by LSF. LPAAT-beta increases both linoleate and linolenate incorporation into PA, which is also reduced by LSF. We conclude that LPAAT and PA remodeling may play a role in diffuse renal toxicity in sepsis due to induction of cellular phenotype changes associated with PA induction by Lipid A and/or LPS. Two human isoforms of LPAAT have been cloned, and apparently address C18 unsaturated acyl chains somewhat selectively. LSF causes functional reduction in LPAAT activity in transfected systems. This does not yet imply a direct effect of LSF on LPAAT. LPAAT and LPS may interact in the membrane in a not-yet-understood manner.

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.

Membranoproliferative glomerulonephritis associated with hepatitis B and C viral infections: from viruslike particles in the cryoprecipitate to viral localization in paramesangial deposits, problematic investigations prone to artifacts.

Membranoproliferative glomerulonephritis (MPGN) is associated with hepatitis C virus infection predominantly in patients with mixed cryoglobulinemia. Viral-like particles reported in cryoglobulins and in glomerular deposits may be artifacts; in situ identification of viral genome or antigens is required to establish validity of such observations. Although the precise role for hepatitis C virus in the pathogenesis of MPGN remains to be determined, recent evidence suggests that chronic infection with hepatitis C virus may stimulate the production of the monoclonal rheumatoid factor in type II cryoglobulins that are deposited in the glomerular lesions. Interferon-alpha now appears to be the drug of choice in treating MPGN associated with hepatitis C virus infection. The association of hepatitis B virus infection with MPGN has not been convincingly established nor has its role in the pathogenesis of MPGN been demonstrated.

Detection of coxsackie B4 virus RNA in infected mouse kidneys by in situ hybridization.

We describe a method for detecting virus-specific RNA sequences using a nonradioactive enzyme system, and analyze coxsackie B4 virus (cox.B4) RNA sequences in infected mouse kidney with pathological changes. Diffuse mesangial proliferation was observed transiently 24 h after inoculation of cox.B4 virus in glomeruli. OCT-treated thin sections of the same tissue were hybridized in situ using a digoxigenin-labeled oligonucleotide probe. The strongest signal was observed in the mesangial sample. These findings suggest that the transient proliferative mesangial changes were caused by direct injury following virus infection without immune complex.

Binding of bacterial adhesins to rat glomerular mesangium in vivo.

Two well characterized bacterial adhesins, the O75X fimbriae of Escherichia coli and the type-3 fimbriae of Klebsiellae, with in vitro affinities to type IV and V collagens, respectively, were used to test whether bacterial components with affinity for glomerular matrix could bind to glomeruli in vivo. The purified fimbrial proteins were injected into rats, and kidney samples were studied by immunofluorescence at two hours to nine months postinjection. The O75X, but not the type-3 fimbriae, formed mesangial deposits that persisted for months. Preincubation of the O75X fimbriae with type IV collagen significantly reduced the glomerular binding. The fimbrial deposits were extracellular, as anti-O75X IgG injected into rats bound to glomeruli. Proteinuria or histological damage could not be detected even after passive or active immunizations of the rats. The results demonstrate that bacterial adhesins may bind in vivo to and persist in glomeruli by their specific affinities. The results also indicate that additional factors provided by the bacteria or the host are needed for glomerular damage to take place.

Diffuse proliferative glomerulonephritis with hepatitis C virus-like particles in paramesangial dense deposits in a patient with chronic hepatitis C virus hepatitis.

A 62-year-old man with hepatitis C virus (HCV) infection developed proliferative glomerulonephritis with IgM and C3 deposits. Electron microscopy showed HCV-like particles in the paramesangial dense deposits, which are similar in shape to HCV previously described. These findings suggest HCV-related proliferative glomerulonephritis.

HIV infects glomerular endothelial and mesangial but not epithelial cells in vitro.

The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells was evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. Infectivity and HIV expression was assessed by: 1) the measurement of p24 antigen production from culture supernatants; 2) the presence of p24 antigen intracellularly by immunofluorescence; 3) levels of P24 antigen production or syncytia formation following the cocultivation of glomerular cells exposed to HIV with normal human peripheral blood mononuclear cells or MT-2 lymphocytes; and 4) the presence of intracellular HIV DNA by polymerase chain reaction. The results indicate that HIV can infect and replicate in glomerular capillary endothelial cells and in a small percentage of mesangial cells, but not in human glomerular epithelial cells in vitro.

Human mesangial cells are resistant to productive infection by multiple strains of human immunodeficiency virus types 1 and 2.

Human immunodeficiency virus-associated nephropathy (HIVAN) is a recognized clinical entity of unknown pathogenesis. A role for viral infection of renal cells in the initiation of this process at present is an intriguing but untested hypothesis. Studies in primate models of acquired immunodeficiency syndrome (AIDS) suggest that injury to the mesangial cell may be central to the sclerosing glomerular lesion characteristic of HIVAN. We therefore tested the infectibility of human mesangial cells (HMC) in vitro by a variety of strains of HIV chosen to include a spectrum of tropisms for different cell types. Productive infection of mesangial cells could not be demonstrated using any of the virus strains. Nonetheless, HIV infection of intrinsic renal cells remains an attractive area of inquiry for understanding the natural history of HIVAN.

Cytomegalovirus infection of human kidney cells in vitro.

To study which structures of a kidney allograft are the main targets for cytomegalovirus (CMV), human glomerular epithelial and mesangial cells, as well as tubular epithelial and endothelial cells were isolated by steel meshes of different pore sizes and enzymatic treatments. The various cultured cell types were characterized by morphology and specific antibodies. Human CMV was inoculated onto cell monolayers using two different culture methods: conventional tissue culture and rapid shell vial culture. To analyze whether CMV had a direct effect on the immunologic properties of kidney parenchymal cells, MHC class I and class II antigen expression was estimated before and after the infection. CMV infected all kidney cells identically. All cells expressed class I strongly after the infection, but they were class I positive prior to infection. Class II antigens were not expressed on the cell surface either before or after the infection. In conclusion, human kidney cells of glomerular, tubular and vascular origin were all infected by CMV without any difference. CMV had no significant direct effects on the antigenic properties of the cells.

Migration of simian virus 40 from the vascular system into the glomerular mesangial region.

The behavior of simian virus 40 (SV40) injected into the vascular system was investigated in the rat glomerulus. The kidney was perfused via the abdominal aorta with a serum-free culture medium for 5 min, with PBS solution containing SV40 and then with the same medium for 15 min at 37 degrees C. In the glomeruli, SV40 particles were detected in the lumen of the capillaries, fenestrations of endothelial cells and lamina rara interna of the glomerular basement membrane. They were also found in the mesangial matrix and mesangial cells. Invaginations of their membrane were observed on several surface areas where SV40 particles were localized close to the surface. Similarly, when the particles were injected into the tail vein, they were detected in the lamina rara interna, the mesangial matrix, and in vacuoles of mesangial cells at 2 h after the injection. These results indicate that SV40 particles migrate from the vascular system into the mesangial matrix, and are then endocytosed in vivo by mesangial cells.

Ultrastructure of kidney from three patients with HBeAg-associated nephropathy with special reference to virus-like particles in the glomerular tufts.

The biopsied kidneys from three patients with hepatitis Be antigen (HBeAg)-associated nephropathy were observed by light microscopy, immunohistochemistry and electron microscopy. By an indirect technique utilizing horseradish peroxidase-conjugated antisera, HBeAg was found to be deposited in a diffuse granular fashion along the glomerular capillary wall. No deposition of hepatitis Bs or hepatitis Bc antigen was detected. The three cases were diagnosed as HBeAg-associated nephropathy. Ultrastructurally, there were finely granular electron-dense deposits in the subendothelial area, basement membrane, mesangial area and subepithelial area of the glomerular tufts. In all three cases, virus-like particles between 30 and 70 nm in diameter were also found in such areas of the glomerular tufts, and rarely in the glomerular capillary lumen and space of Bowman. They occasionally formed clusters in the phagosomes of mesangial cells. In addition, tubulo-reticular structures were noted in the cytoplasm of endothelial cells in the glomerular capillaries. The presence of HBeAg both in the serum and in the kidney and of virus-like particles in the glomerular tufts suggests that HBeAg is causally related to the development of HBeAg-associated nephropathy.

Cytomegalovirus replicates efficiently in human kidney mesangial cells.

Human cytomegalovirus (HCMV) is a major renal pathogen in congenitally infected infants and renal allograft recipients. We postulated that a specific renal cell type was involved in HCMV infection and reactivation. Human fetal kidney cortex cell cultures were assayed for their ability to support HCMV infection. Infectious center assays indicated that the low level of viral replication observed by virus yield assay occurred from a fraction of the cells in the mixed cultures. Virus-specific immunofluorescence and in situ hybridization documented the presence of HCMV-specific protein and nucleic acid, respectively, in a morphologically distinct cell type. These cells were purified, were identified as kidney mesangial cells, and were observed to support efficient HCMV replication. Our research identifies mesangial cells as a renal cell type that supports HCMV replication and provides evidence to implicate these cells in the pathogenesis of HCMV-induced renal disease.