Glomerular binding sites for peanut agglutinin in acute poststreptococcal glomerulonephritis

Streptococcal neuraminidase may be responsible for the development of auto-immune reactivity in acute poststreptococcal glomerulonephritis (APSGN). Neuraminidase may react with immunoglobulins in the circulation and with sialic acid-rich sites in the endothelial and epithelial glomerular capillary, therefore, extrinsic or intrinsic sialic acid-depleted substrate may be localized in the glomeruli. We studied renal biopsies from 17 patients with APSGN, 48 patients with other renal pathologies and 2 normal kidneys for the capacity to bind fluorescein-labelled peanut agglutinin (PNA) lectin. PNA has specificity for galactosyl radicals which are exposed after sialic acid removal. We similarly studied the kidneys of rats at intervals ranging from hours to 32 days after an intravenous injection of 0.02 units of neuraminidase per g of body weight. Five biopsies of APSGN patients and 2 biopsies from patients with renal pathologies different from APSGN showed glomerular PNA binding. Of APSGN patients, 4 corresponded to the 5 patients biopsied within 30 days of the beginning of the disease and only 1 biopsy was positive in the 12 patients who were biopsied later. The PNA binding predominated in the mesangium and the pattern was irregular and speckled. These findings suggest that sialic-acid depleted material is present in the glomeruli, early in the course of APSGN.     

Humoral immunity to streptococcal antigen in acute and chronic glomerulonephritis

A study was carried out to verify the clinical usefulness of the elaborated method for the measurement of antistreptococcal antibody in revealing the streptococcal etiology of glomerulonephritis.In 158 patients with glomerulonephritis antistreptococcal antibody (ASA), circulating immune complexes (CIC) and haemolytic activity of the complement were measured.On the basis of immune complex formation it has been concluded that streptococcal infection may cause glomerulonephritis. Serial determinations of ASA and CIC are helpful in establishing the streptococcal etiology of glomerulonephritis and in monitoring the course of the disease.     

Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet

Considerable insight has been gained into the etiopathogenesis of poststreptococcal glomerulonephritis since the landmark theoretical construct of Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever. Over the years, molecular mimicry between streptococcal products and renal components, autoimmune reactivity and several streptococcal antigens have been extensively studied. Recent investigations assign a critical role to both in situ formation and deposition of circulating immune complexes that would trigger a variety of effector mechanisms. Glomerular plasmin-binding activity of streptococcal glyceraldehyde-3-phosphate-dehydrogenase may play a role in nephritogenicity and streptococcal pyrogenic exotoxin B and its zymogen precursor may be the long-sought nephritogenic antigen.     

Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo

In an attempt to further study the possible contribution of circulating immune complexes (CIC) in the pathogenesis of acute poststreptococcal glomerulonephritis, 61 patients with APSGN were studied during the first three weeks of the disease, and 13 patients with noncomplicated streptococcal impetigo as a control group. C1q solid phase ELISA and Conglutinin (K) solid phase ELISA were used to measure the levels of immune complexes. The incidence of CIC in a single serum sample from patients with APSGN was 48%. Elevated levels of immune complexes were found in 46% of the patients with streptococcal impetigo. The absolute levels of CIC were comparable in both groups of patients. No correlation was found among the presence of CIC and the clinical, immunoserological or pathological findings of the disease. Our results do not support the hypothesis that trapping of the circulating immune complexes play an important role on the renal injury poststreptococcal infection. Instead, we suggest that CIC are an epiphenomena present in APSGN, and may represent rather a systemic inflammatory immune response in patients with group A streptococcal infection.     

Cationic antigens in poststreptococcal glomerulonephritis

Antigen charge is an important factor in the pathogenesis of experimental immune complex glomerulonephritis. Its potential role in man was investigated in post-streptococcal glomerulonephritis, a disease where the causative agent is known. Cationic, extracellular streptococcal antigens were detected in 8 of 18 renal biopsies from patients with acute poststreptococcal glomerulonephritis (APSGN). The antigen was found mainly in earlier biopsies in which both IgG and IgM were present. Patients' sera taken at the time of biopsy contained antibody to cationic, streptococcal antigens. Cationic moieties are known to have affinity for the glomerular basement membrane and it is possible that the type of antigen described here initiates APSGN via in situ immune complex formation.     

Nitric oxide and glomerulonephritis

Glomerulonephritis is a common clinical condition that is caused by immune-mediated injury to the kidney and is characterized by dysfunction of the glomerular capillary filtration barrier. Nitric oxide (NO), a ubiquitous molecule with many biological functions throughout the body, has been evaluated as an inflammatory mediator in these circumstances. NO may induce glomerular injury directly or may act via stimulation of a host of other inflammatory mediators. A variety of experimental models of glomerulonephritis have been studied including those induced by infusion of antibodies to the Thy1.1 antigen or glomerular basement membrane, Heymann nephritis, and autoimmune nephritis. In virtually all of these cases there is evidence of increased NO production. Excessive production of NO by inducible nitric oxide synthase (iNOS), derived from infiltrating immune cells or resident glomerular cells, nearly always is associated with increased glomerular injury. Interventions that inhibit this enzyme result in less proteinuria and diminished glomerular damage. In contrast, NO derived from endothelial nitric oxide synthase (eNOS) may limit glomerular disease by preserving endothelial cell integrity. There are only a limited number of studies that have evaluated the impact of NO in patients with glomerulonephritis. Although the bulk of evidence supports a role of NO as a pro-inflammatory mediator in glomerulonephritis, additional work is needed to show an association between altered NO production and the severity and outcome of disease in patients with this disease. It is hoped that better understanding of the role of NO in glomerulonephritis will lead to the development of therapies to ameliorate the disease.     

IgG, IgA and IgM rheumatoid factors in patients with glomerulonephritis

Rheumatoid factors (RF), autoantibodies to IgG, have been postulated to have some pathogenetic role in the development of some types of glomerulonephritis. A simple and sensitive solid-phase fluorescence immunoassay was employed to determine whether IgG, IgA and IgM RF were detectable in sera from patients with various types of glomerulonephritis, rheumatoid arthritis (RA) and those with various streptococcal infections. IgG, IgA and IgM RF were significantly increased in the majority of patients with RA, lupus nephritis (SLE), acute poststreptococcal glomerulonephritis (APSGN) and various streptococcal infections. The titers of IgG and IgA RF were significantly higher in patients with APSGN than in those with simple pharyngitis. IgM RF was increated in patients with IgA nephropathy (IgA-N) and in those with membranoproliferative glomerulonephritis type I (MPGN). No significantly high RF was observed in membranous nephropathy (MN) or chronic mesangial proliferative glomerulonephritis without IgA deposition (PGN). It is suggested that some autologous immune mechanisms may be involved in the pathogenesis of some types of glomerulonephritis.     

Acute glomerulonephritis with bacteriuria: a probable etiologic relationship

Twenty-one cases of acute glomerulonephritis in children with no previous history of renal disease were studied. Urinary infection with a rising titre of serum agglutinins against the organisms isolated from urine was found in 5 cases. No evidence of previous streptococcal infection was found in these cases. In the meantime all 8 cases with post-streptococcal glomerulonephritis remained without bacteriuria. In one case acute glomerulonephritis followed virus hepatitis, and in the remaining 7 cases the cause of glomerulonephritis was unknown. It is suggested that in predisposed patients the bacteria present in urinary infections might act as antigens starting immunologic reactions in the glomeruli, leading to glomerulonephritis. The final proof of this theory awaits immunofluorescence identification of these antigens in the glomeruli.     

Renal histological studies in patients with Takayasu's arteritis. Report of 3 cases

Clinical findings and structural alterations of the kidney in 3 patients with Takayasu's arteritis (TA) and associated glomerulonephritis are described. Clinical evidence of renal disease included persistent proteinuria and microscopic hematuria in all patients. Renal histology showed proliferative glomerulonephritis in 2 of the 3 patients. In 1 patient in whom sequential examination of the kidney was possible, glomerular changes had progressed in severity, in parallel with the expansion of arterial damage of TA. Prednisolone therapy induced a complete disappearance of systemic symptoms of TA and an improvement of proteinuria and hematuria. These findings suggest that TA, which quite possibly results from an immune response to disseminated antigen(s), may occasionally induced glomerulonephritis as a part of its histological expression.     

Use of radioimmunoassay for the detection of circulating antistreptococcal antibody in patients with glomerulonephritis

A method of radioimmunologic quantitation of antibodies to streptococcal antigen separated from the cell wall extract of group A type T₁₂ strain has been developed. The highest values of radioactive antigen binding were observed in acute glomerulonephritis (75%), as compared to chronic glomerulonephritis in which values of 25% to 56% were found depending on the morphology of renal changes. It was shown that none of the patients with pyelonephritis, Alport's syndrome, lupoid nephritis and polycystic renal disease had elevated antistreptococcal antibody levels. In contrast to this, all patients with tonsillitis and proteinuria exhibited increased titre of this antibody.It was shown that the antigen is related neither to M-protein nor to group A polysaccharide and that it is not type-specific because the binding of antigen T₁₂ may be inhibited by the antigen produced from strain T₅. Although the antigen is not type-specific, some differences in the response to antigens prepared from various types of streptococci in patients with different form of chronic glomerulonephritis are observed.     

Pathogenesis of hepatitis C virus-associated glomerulonephritis

Summary: Hepatitis C virus (HCV), in addition to causing both acute and chronic liver disease, may also be associated with several immunologically-mediated syndromes, particularly cryoglobulinaemia and membranoproliferative glomerulonephritis. Although the glomerulonephritis may be a feature of a systemic cryoglobulinaemic syndrome, it may also present as a primary renal disease without evidence of vasculitis or liver disease. Most of these latter patients, however, will have detectable cryoglobulinaemia either at the time of presentation or with continued observation. In this review, we discuss the pathogenesis of the glomerular disease. Most evidence supports the hypothesis that HCV associated glomerular disease results from the deposition of circulating immune complexes that are usually cryoprecipitable and which contain HCV, anti-HCV IgG, and rheumatoid factors. However, HCV antigens have yet to be identified in glomerular biopsies. This has raised the possibility that other pathogenic mechanisms may be involved, including auto-antibodies directed against glomerular antigens and factors related to chronic liver disease. Further studies are necessary to fully elucidate the pathogenesis of this recently recognized disease.     

Lymphocytotoxic antibodies and antiglobulins in renal allograft recipients. Correlative study with acute rejection.

In 45 patients who received kidney transplants, both homologous and heterologous human antiglobulins (anti-Ig) and HLA cytotoxic antibodies have been studied before and after transplantation and in some cases after nephrectomy. A similar study has been performed in a control group of 1,019 healthy blood donors and in 130 patients with acute or chronic glomerulonephritis. After transplantation, homologous anti-IgG were found in 60% of the patients, as compared with 3.5% in the healthy blood donors and 21% in patients with various forms of glomerulonephritis. This difference is particularly striking in sera obtained prior to nephrectomy; the presence of anti-IgG and cytotoxic antibodies in the same patient being significantly associated with early transplant failure. Anti-IgA were found in 75% of the patients with transplants and in 37% of the patients with glomerulonephritis. There was no relationship between the anti-IgA and the outcome of the graft. On the other hand, heterologous anti-Ig were unchanged in the three groups investigated. The mechanism of formation of the anti-IgG is not clear. They are probably antibodies against antigenic structures of the patient's own antibodies, previously combined with a soluble antigen or an antigen on the transplant that has undergone molecular transformation in the course of this reaction. Their pathogenic role, although not demonstrated, can be strongly suspected, and, in a practical way, screening for the anti-Ig in kidney transplant recipients could be of value as a prognostic test.     

The future of nephrologic research: significance and urgent problems

The problems in the diagnosis and especially the pathogenetic mechanism of IgA nephropathy are discussed and suggestions are made that this entity may not be a renal disease of primary renal immunogenetic origin but may be a disease of disturbed mesangial transport mechanism for IgA. Suggestions are made for intensive studies on the pathogenesis and differential diagnosis of focal glomerulosclerosis vs. minimal change disease (lipoid nephrosis) especially by immunohistology and T Cell sub-set abnormalities. It is suggested to study minimal change disease from the viewpoint of a T Cell immunodeficiency with lymphokines as a permeability changing factor. Depressed antibody formation in such partially immunodeficient patients may be important for differential diagnosis from other nephrotic stages. The immunology of acute glomerulonephritis as caused by cytoplasmic streptococcal antigens requires further study together with resultant chronic glomerulonephritis on an auto-antibody basis. The disputed merits of plasmapheresis require further detailed studies. The investigation of the suggested importance of nephrectomies on the renal function of kidney donors is of utmost importance in view of its relation to the future of live donor transplantations.     

Pathogenic mechanisms in membranoproliferative glomerulonephritis

PURPOSE OF REVIEW: This review considers new information on the pathogenesis of a long recognized and poorly understood form of glomerular injury, membranoproliferative glomerulonephritis. This disease has received growing attention as it is the principal renal manifestation of hepatitis C virus infection, which has become pandemic worldwide. RECENT FINDINGS: This review briefly describes three murine models of membranoproliferative glomerulonephritis suitable for pathogenesis studies. We consider recent evidence implicating innate immune mechanisms in immune and autoimmune-mediated glomerulonephritis, and recent data pointing to the alternative pathway of complement activation in the amplification of glomerulonephritic injury. SUMMARY: Understanding the contribution of complement activation and innate immunity to the evolution of membranoproliferative glomerulonephritis promises to provide new therapeutic targets for this disease. Inhibitors of the complement cascade are already being tested in clinical trials as therapeutic interventions for some human glomerular diseases. Successful tests of this approach in membranoproliferative glomerulonephritis are still awaited. Our understanding of how the innate immune system modulates glomerulonephritis is still in an early stage, and future studies should be directed at identifying targets and specific interventions that may also benefit patients with this disease.     

Acute presentation and persistent glomerulonephritis following streptococcal infection in a patient with heterozygous complement factor H-related protein 5 deficiency

Acute poststreptococcal glomerulonephritis is a common cause of acute nephritis in children. Transient hypocomplementemia and complete recovery are typical, with only a minority developing chronic disease. We describe a young girl who developed persistent kidney disease and hypocomplementemia after a streptococcal throat infection. Kidney biopsy 1 year after presentation showed isolated glomerular complement C3 deposition, membranoproliferative changes, and subendothelial, intramembranous and occasional subepithelial electron-dense deposits consistent with C3 glomerulopathy. Complement gene screening revealed a heterozygous single nucleotide insertion in exon 4 of the complement factor H-related protein 5 gene (CFHR5), resulting in a premature stop codon. This variant was not detected in 198 controls. Serum CFHR5 levels were reduced. The mother and sister of the index patient were heterozygous for the sequence variant, with no overt evidence of kidney disease. We speculate that this heterozygous CFHR5 sequence variant is a risk factor for the development of chronic kidney disease after streptococcal infection.     

A new hypothesis about the pathogenesis of chronic glomerulonephritis

Extensive trials have been done to find a relationship between chronic glomerulonephritis and streptococcal tonsillitis. Serological, epidemiological and other studies failed to prove this relationship in the majority of instances. We have observed that definite evidence of pyelonephritis, with disparity between the function of both kidneys and bacteriuria, was present in a large number of the cases diagnosed histologically of the kidney can lead to a proliferative glomerulopathy. We suggest that previous haematogenous renal parenchymal infection or pyelonephritis is responsible for the glomerulopathy of many of the cases diagnosed as chronic glomerulonephritis of unknown etiology or presumably related to streptococcal tonsillitis or the so-called subclinical acute poststreptococcal glomerulonephritis.     

HIV-associated immune complex glomerulonephritis with "lupus-like" features: a clinicopathologic study of 14 cases

BACKGROUND: While the most common glomerular lesion associated with human immunodeficiency virus (HIV) infection is collapsing focal segmental glomerulosclerosis (FSGS) [HIV-associated nephropathy (HIVAN)], immune complex-mediated forms of glomerulonephritis have been increasingly reported. One form of glomerulonephritis that has been described in the HIV-infected population is immune complex glomerulonephritis with "lupus-like" features, characterized by histologic, immunohistologic, and ultrastructural features resembling lupus nephritis, but occurring in patients without evidence of systemic lupus erythematosus (SLE). Data regarding clinical outcomes in patients with this form of glomerulonephritis are very limited. METHODS: We reviewed pathology reports for all native renal biopsy specimens from HIV-positive patients processed at our center from January 1999 through December 2003. Of 77 total specimens, 14 met the following criteria for lupus-like glomerulonephritis: (1) immunofluorescence microscopy showed granular glomerular staining for IgG, IgA, IgM, C3 and C1q, with > or=1+ (0 to 4+ scale) staining for C1q; and (2) the patient's serum was negative for antinuclear antibodies (ANA), or weakly positive (titer < or =1:80) for ANA and negative for antidouble-stranded DNA. RESULTS: Clinically, ten of the 14 patients with lupus-like glomerulonephritis presented with nephrotic syndrome, all had microscopic hematuria, and nine had serum creatinine >3.0 mg/dL. All but one were African American. Histologically, seven biopsies showed diffuse proliferative glomerulonephritis, six focal proliferative glomerulonephritis, and one membranous nephropathy. All but two biopsies showed moderate or severe chronic change, and three showed concurrent HIVAN. Ten of the 14 patients developed end-stage renal disease (ESRD) within 1 year of the biopsy. Nine of these ten patients presented with proteinuria >5.0 g/24 hours and nephrotic syndrome, while three of four patients who did not develop ESRD had proteinuria < or =3.0 g/24 hours. CONCLUSION: Lupus-like glomerulonephritis, defined by immunohistologic features and absence of serologic evidence of SLE, is not an uncommon form of glomerular disease in HIV-infected patients undergoing a renal biopsy. Renal outcomes in these patients were poor, although this may be due largely to most patients presenting with advanced disease.     

Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.     

Association of overt glomerulonephritis and liver disease: a study of 34 patients.

Thirty-four patients with overt glomerulonephritis and chronic liver disease were studied. Kidney specimens were examined by light, electron and immunofluorescence microscopy. Plasma C3 levels were measured and a search for cryoglobulinemia was carried out in all patients. Twenty-six out of the thirty-four patients had an immune complex type glomerulonephritis (membrano-proliferative glomerulonephritis or glomerulosclerosis with mesangial deposits) suggestive of hepatic glomerulonephritis. The glomerular deposits almost always contained IgA and very frequently other immunoglobulins as well as C3. The membrano-proliferative glomerulonephritis was characterized by severe renal symptoms, mixed cryoglobulinemia and the frequent finding of low C3 levels. These data suggest that there is a linkage between liver disease and glomerulonephritis. The immunomorphological type of glomerulonephritis and the cryoglobulinemia are both suggestive of an immune complex disease. The lowering of the C3 levels could be due to activation of complement components by immune complexes, to hepatic hyposynthesis, or to a combination of the two.     

Renal involvement in bone marrow transplantation

Bone marrow transplantation (BMT) is an effective therapeutic strategy for leukaemic malignancies and depressed bone marrow following cancer. However, its side effects on kidneys have been reported. Some drugs and irradiation are also suggested to be nephrotoxic. It is well known that haemolytic uraemic syndrome (HUS) after BMT develops as late-onset BMT nephropathy. Cyclosporine A (CsA) is a possible cause. Radiation nephropathy shows changes that are similar to the histology of HUS. These findings suggest that endothelial damage is closely associated with the pathogenesis of post-BMT nephropathy. Recently, some patients have developed glomerulonephritis accompanied by graft-versus-host disease (GVHD) after BMT. In these patients immune deposits are found mainly in subepithelium and mesangium equal to those of secondary membranous glomerulonephritis. A murine experimental model of GVHD manifests similar symptoms and histological changes to those of actual patients and may suggest the pathogenesis of glomerulonephritis.