Proliferative Immune Complex Glomerulonephritis Research Articles

Correlation of Red Blood Cell Casts With Renal Dysfunction in Patients With Infection-Related Glomerulonephritis.

Infection-related glomerulonephritis (IRGN) usually manifests as a proliferative immune-complex glomerulonephritis. The degree of renal dysfunction at presentation can vary. Association with histologic features on kidney biopsy remains unknown. To study the correlation between renal function in IRGN at the time of biopsy and the severity of histologic features. Culture-proven IRGN cases at our facility were included and divided based on estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m2. Patients' demographic and pathologic findings were obtained from electronic medical records and kidney biopsy reports. In total, 104 cases were diagnosed with IRGN on biopsy (mean age, 55.6 ± 15.6 years; male, n = 79 [76%]; median eGFR, 14.5 mL/min/1.73 m2), and 51 of 104 showed eGFR <15 mL/min/1.73 m2. Among all the histologic features assessed, only percent tubules with red blood cell (RBC) casts showed statistical difference, being significantly higher in the lower-eGFR group (P = .004). Multivariable logistic regression analysis also showed that %tubules with RBC casts were associated with lower eGFR (odds ratio, 1.12; 95% CI, 1.01-1.24; P = .01). Patients with 5% or more RBC casts (n = 31) showed a lower eGFR (P = .02) and a higher %cellular crescent (P < .001) compared with those with less than 5% RBC casts. Patients with concomitant anticoagulant therapy (n = 11) showed higher percentages of RBC casts than those without anticoagulants (P = .02). Particular attention to the extent of RBC casts on kidney biopsy is recommended in patients with IRGN because these portend worse renal dysfunction, more so in patients requiring anticoagulation (including for hemodialysis) because they are especially vulnerable to developing anticoagulant-related nephropathy.

Programmed death 1 and its ligands do not limit experimental foreign antigen-induced immune complex glomerulonephritis.

Interactions between the co-stimulatory molecule programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, constrain T-cell responses and help maintain peripheral tolerance. Glomerulonephritis can result from a variety of antigens, both self and foreign, and from humoural and cellular effector responses. These studies aimed to define the role of PD1 and its ligands in circulating immune complex glomerulonephritis induced by immunity to a foreign antigen. Immune complex glomerulonephritis was initiated by injecting BALB/c mice with horse spleen apoferritin intraperitoneally daily for 14 days. Inhibitory anti-mouse PD-1, anti-PD-L1 or anti-PD-L2 antibodies were administered every other day. Renal disease and immune responses were studied. Daily injection of horse spleen apoferritin-induced proliferative immune complex glomerulonephritis in control antibody-treated mice, but inhibiting PD-1 did not augment renal injury. Specifically, blocking PD-1 did not increase serum antigen-specific antibodies or increase glomerular immunoglobulin G deposition, the hallmark of injury in this model. Furthermore, C3 deposition was unaffected and glomerular macrophages were reduced after anti-PD-1 antibodies. However, anti-PD-1 administration did increase splenocyte proliferation and cytokine production including interferon-γ, interleukin (IL)-4, and IL-17, but not IL-10. Neutralizing either PD-L1 or PD-L2 alone did not result in major alterations in renal injury. The endogenous PD-1/PD-L pathway does not limit acute experimental foreign antigen-induced circulating immune complex glomerulonephritis.

Fraternal twins with job's syndrome and immune complex nephritis.

Job's syndrome or autosomal dominant hyperimmunoglobulin E syndrome (Hyper-IgE) is a rare disorder that results from a STAT3 gene mutation, which results in the absence of T-helper 17 (Th17) cells and manifests as a severe immunodeficiency. Affected individuals suffer recurrent soft tissue and pulmonary infections among other manifestations, and the spectrum of the disease is still being characterized. We describe 2 sisters with Job's syndrome each with variable expressivity. However, both patients developed proteinuric kidney disease and had biopsies confirming the presence of immune complex glomerulonephritis with staining for immunoglobulins and complement components. Previous reports link Job's syndrome and the development of systemic lupus erythematosus (SLE), but proliferative immune complex glomerulonephritis has not been described. We speculate that continual internal and external antigen exposure may induce an autoimmune process similar to SLE, which in turn may account for the immune complex disease in the kidney.

4SC-101, A Novel Small Molecule Dihydroorotate Dehydrogenase Inhibitor, Suppresses Systemic Lupus Erythematosus in MRL-(Fas)lpr Mice

Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase (DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.

Mononuclear cells in glomeruli and cytokines in urine reflect the severity of experimental proliferative immune complex glomerulonephritis

Immunohistochemical methods were used to investigate the role of macrophages in the progression of proliferative immune complex glomerulonephritis. The mononuclear cell component of glomerular inflammation was analysed in three different stages of chronic serum sickness, each of which was clearly distinguished by criteria of kidney function. Urinary excretion of the macrophage secretory products interleukin-1 and tumour necrosis factor was also evaluated in relation to the functional severity of kidney disease. T lymphocytes and macrophages began to accumulate in glomeruli at the onset of proteinuria, but not before. Urinary excretion of interleukin-1 also began with proteinuria. Proteinuria increased in direct correlation with increases in the number of glomerular macrophages. Development of the most severe stage of glomerulonephritis, characterized by cachexia, declining kidney function, and necrotizing glomerular pathology, was accompanied by the disappearance of T cells from glomeruli and the expression of highly abnormal phenotypes by most macrophages. In addition, there was a switch from urinary excretion of interleukin-1 to excretion of tumour necrosis factor. The progression of proliferative immune complex glomerulonephritis was associated with qualitative as well as quantitative changes in glomerular macrophage populations. Differentiation and/or activation of those glomerular macrophages may have resulted from local T cell-mediated immunoregulation. Measurements of urinary cytokine excretion provided a reliable means of monitoring disease progression. The local action of tumour necrosis factor probably contributed to declining kidney function in the most severe stage of disease.

Expression and activation of STAT3 in chronic proliferative immune complex glomerulonephritis and the effect of fosinopril

Signal transducers and activators of transcription (STATs) are cytoplasmic proteins that are activated in response to stimulation from various cytokines. Among these, STAT3 is an important member that has been implicated in the inflammatory proliferation of cells. We hypothesized that STAT3 may be activated in kidneys of rats having modified chronic immune complex glomerulonephritis, and that angiotensin-converting enzyme (ACE) inhibition with fosinopril may prevent the activation of STAT3 and subsequent upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1), which are effects that may explain the therapeutic effects of fosinopril on nephritis. Fifty-one Wistar rats were randomly divided into three groups that included a control group, a model group and a fosinopril group. Bovine serum albumin (BSA) nephritis was induced by subcutaneous immunization and daily intraperitoneal (i.p.) administration of BSA. To accentuate the nephritis, we performed uni-nephrectomy and gave 100 microg of lipopolysaccharide (LPS) as an i.p. injection. Macrophage infiltration (ED-1) was assessed with immunohistochemistry. The expression and activation of STAT3 and the expression of TIMP-1, one of the STAT3 downstream genes, were observed in renal tissues of rats by means of immunohistochemistry, electrophoretic mobility shift assay (EMSA), western blot and northern blot. The relationships between STAT3 phosphorylation, 24 h urinary protein excretion and TIMP-1 expression were also analysed. Northern blot showed that the mRNA expression of both STAT3 and TIMP-1 was significantly increased in kidneys from the model group, but significantly decreased in the fosinopril group (P<0.05). Western blot analysis revealed similar increases in the expression of STAT3, phospho-STAT3 (p-STAT3) and TIMP-1 in the model group. Analysis of immunohistochemistry showed that STAT3 and p-STAT3 were expressed in very few cells of normal rats, that expression was strong in model rats and that this increased expression was attenuated in the fosinopril group (P<0.05). The expression of p-STAT3 in glomeruli was positively correlated with 24 h proteinuria as well as with glomerular TIMP-1 expression. Double staining showed that some ED-1-positive cells also contained p-STAT3-positive staining. The present study showed that STAT3 is expressed and activated in kidneys of rats with modified immune complex glomerulonephritis. These rats also had increased ED-1-positive cells, with some cells showing simultaneous expression of p-STAT3 and ED-1, which may contribute to glomerular inflammatory proliferation and extracellular matrix accumulation. Finally, fosinopril downregulated STAT3 activation and ED-1 influx, which are effects that may attenuate renal damage in this model.

Autoimmunity and glomerulonephritis in mice with targeted deletion of the serum amyloid P component gene: SAP deficiency or strain combination?

Human serum amyloid P component (SAP) binds avidly to DNA, chromatin and apoptotic cells in vitro and in vivo. 129/Sv x C57BL/6 mice with targeted deletion of the SAP gene spontaneously develop antinuclear autoantibodies and immune complex glomerulonephritis. SAP-deficient animals, created by backcrossing the 129/Sv SAP gene deletion into pure line C57BL/6 mice and studied here for the first time, also spontaneously developed broad spectrum antinuclear autoimmunity and proliferative immune complex glomerulonephritis but without proteinuria, renal failure, or increased morbidity or mortality. Mice hemizygous for the SAP gene deletion had an intermediate autoimmune phenotype. Injected apoptotic cells and isolated chromatin were more immunogenic in SAP(-/-) mice than in wild-type mice. In contrast, SAP-deficient pure line 129/Sv mice did not produce significant autoantibodies either spontaneously or when immunized with extrinsic chromatin or apoptotic cells, indicating that loss of tolerance is markedly strain dependent. However, SAP deficiency in C57BL/6 mice only marginally affected plasma clearance of exogenous chromatin and had no effect on distribution of exogenous nucleosomes between the liver and kidneys, which were the only tissue sites of catabolism. Furthermore, transgenic expression of human SAP in the C57BL/6 SAP knockout mice did not abrogate the autoimmune phenotype. This may reflect the different binding affinities of mouse and human SAP for nuclear autoantigens and/or the heterologous nature of transgenic human SAP in the mouse. Alternatively, the autoimmunity may be independent of SAP deficiency and caused by expression of 129/Sv chromosome 1 genes in the C57BL/6 background.

Monocyte Chemoattractant Protein-1 in Chronic Proliferative Immune Complex Nephritis

In rats with chronic serum sickness, proliferative immune complex glomerulonephritis progresses in three discrete stages, designated mild, moderate, and severe. One distinguishing immunopathologic feature, the progressive increase in the number of glomerular macrophages, is closely correlated with decreasing kidney function. We hypothesized that monocyte chemoattractant protein-1, a β-subfamily chemokine with potent monocyte-specific chemotactic activity, might contribute to this macrophage accumulation. Immunohistochemical methods were used to identify monocyte chemoattractant protein-1 in kidney tissue sections. Total RNA was extracted from the kidneys of rats at each stage of chronic serum sickness, and age-matched controls, and Northern blot analysis was performed with a rat monocyte chemoattractant protein-1 cDNA probe. Tissue staining localized monocyte chemoattractant protein-1 to the glomerular capillary wall and mesangium in chronic serum sickness. Minimal quantities of monocyte chemoattractant protein-1 mRNA were detected in the kidneys of normal control rats, with marked increases in mRNA as chronic serum sickness nephritis progressed to the moderate stage. There was then an apparent decrease in monocyte chemoattractant protein-1 mRNA in the severe stage. The degree of protein staining and mRNA levels paralleled each other. We conclude that monocyte chemoattractant protein-1 is a potentially important chemotactic agent in chronic serum sickness nephritis.

Glomerular macrophage phagocytic activity in experimental immune complex nephritis

In rats with the proliferative immune complex glomerulonephritis of chronic serum sickness, kidney function deteriorates in three clearly distinguishable and discrete stages: mild, moderate and severe. The macrophage component of glomerular inflammation in each stage is also quantitatively and qualitatively distinct, with abnormal phenotypic markers appearing in the moderate stage and increasing in the severe stage. To determine whether there were distinct functional differences among macrophages from the three stages, Fc gamma receptor-mediated phagocytic capacity was measured. The phagocytic capacity of glomerular macrophages increased significantly in the moderate stage, then significantly decreased, as rats progressed to severe chronic serum sickness. This decline in phagocytic function was not associated with a decrease in the expression of Fc gamma receptors on the glomerular macrophage cell surface. Furthermore, the phagocytic function of peritoneal macrophages from rats with severe chronic serum sickness was not impaired. Whether or not this attenuation of glomerular macrophage phagocytic capacity is the cause, or result, of renal disease progression remains unclear. It may indicate a potentially protective role for intraglomerular macrophages, and can serve as an additional functional marker of disease progression.

The Effect of Cyclosporin A on Disease Progression in Proliferative Immune Complex Glomerulonephritis

In rats with the proliferative immune complex glomerulonephritis of chronic serum sickness, kidney function deteriorates in three discrete and readily distinguishable stages: Mild, Moderate, and Severe. The mononuclear cell composition of glomerular inflammation is also different in each stage. The immunosuppressive drug, cyclosporin A, was administered to rats with chronic serum sickness in order to investigate the relationship between glomerular immunopathology and pathophysiology in proliferative immune complex nephritis. When introduced after the onset of proteinuria, daily treatment with cyclosporin A failed to prevent the progression from Moderate to Severe nephritis, which is characterized by the abnormal differentiation and local proliferation of glomerular macrophages, as well as grave deterioration in kidney function. In contrast, when cyclosporin A therapy started before the onset of proteinuria, the course of proliferative glomerulonephritis was altered significantly. Although the levels of proteinuria and macrophage accumulation that are characteristic of the Moderate stage of nephritis were not reduced, progression to Severe nephritis did not occur. The number of glomerular macrophages appeared to increase in two separate phases in this chronic serum sickness model of proliferative immune complex glomerulonephritis. The first phase, which coincided with the onset of proteinuria, did not require T cells and culminated only in moderate hypercellularity and proteinuria. The second increase in the number of glomerular macrophages, which was accompanied by the expression of abnormal macrophage phenotypes, was closely linked to the development of severe kidney insufficiency. The protective effect of cyclosporin A therapy was consistent with, although not conclusive proof for, the hypothesis that local T cell activation may contribute to the progression of proliferative immune complex glomerulonephritis. Since cyclosporin A can also directly influence the responses of macrophages and mesangial cells, the effect of the drug on the course of nephritis in this model might not be related to its immunosuppressive action.

Antibody response and antibody affinity maturation in cats with experimental proliferative immune complex glomerulonephritis

An experimental model of proliferative glomerulonephritis (GN) in the cat, which closely resembles human proliferative forms of GN, has been used to study the role of antibody and antibody affinity in the development of immune complex-mediated renal disease. The serum IgG and IgM antibody response to antigen, average antibody affinity (avidity) and affinity heterogeneity of the IgG and IgM populations was assessed at varying times after commencement of chronic immunization with the antigen, human serum albumin (HSA), by enzyme immunoassay. Cats could be classified according to whether they were “low”, “intermediate” or “high” IgG responders, by quantification of serum IgG values. Cats with the lowest serum IgG values failed to develop glomerulonephritis. However, there was no relationship between actual IgG values and the severity of the induced disease. In contrast to IgG, there was no division of cats into low or high IgM anti-HSA responders. Again, cats with the lowest IgM values failed to develop GN, but, more interestingly, a late, marked increase in serum IgM anti-HSA occurred only in cats that developed clinical signs of GN (anterior uveitis and nephrotic syndrome). Maturation of average, functional IgG affinity (avidity) for HSA following chronic immunization was clearly demonstrated for all cats. At the end of the experiment, all cats had IgG of high affinity for HSA and the average affinity heterogeneity of the IgG populations was less than in measurements taken earlier. Values of IgG affinity at the end of the experiment were very similar both in cats which developed GN and in those which remained clinically, biochemically and pathologically normal. In contrast to IgG antibody, some cats developed IgM of increased affinity, whilst others produced antibody of reduced affinity, following chronic immunization. There was no correlation between the development of disease and the production of either low or high affinity IgM antibody. Data indicated that an alteration in IgM affinity occurred at a late stage, as serum IgM levels increased, in cats which progressed to develop GN. These findings suggested that an increase in both serum IgG and IgM anti-HSA values, in particular IgM, was associated with the development of a more severe immune complex renal disease in these cats. Although there was no evidence that differences in the average affinity of either the IgG or IgM antibody populations for HSA, were associated with the development of disease, the increase in IgM values was also accompanied by a concomitant alteration in IgM affinity for antigen. Such alteration in IgM preceded the development of proteinuria and clinical signs of GN by 4 to 5 weeks and appeared to be indicative for the development of proliferative GN in this feline model of GN.