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Background Idiopathic intracranial hypertension (IIH) is defined by an increased cerebrospinal fluid pressure in the absence of inflammation, structural obstructions, or mass lesions. Although the underlying pathogenesis of IIH is not fully understood, associations with specific risk factors as obesity, obstruction of cerebral venous sinuses, medications, endocrine or systemic conditions and chronic kidney disease have been described. Immune-complex glomerulonephritis as IgA-nephropathy is a frequent cause of chronic kidney failure, which was reported previously in one IIH patient. To date, there is no knowledge about the variable relation of immune-complex nephritis, kidney function and the course of IIH. Case presentation We report three cases (two females) of concurrent diagnosis of IIH and immune-complex glomerulonephritis. All patients presented with typical IIH symptoms of headache and visual disturbances. Two patients had been diagnosed with IgA-nephropathy only few weeks prior to IIH diagnosis. The third patient had been diagnosed earlier with terminal kidney failure due to a cryoglobulin glomerulonephritis. Conclusion We propose a possible link between renal deposition of immune-complexes and increased cerebrospinal fluid pressure. Pathophysiological hypotheses and clinical implications are discussed. We recommend clinical awareness and further systematic research to obtain more information on the association of IIH and immune-complex glomerulonephritis.

There is limited data on the etiology, clinical and histopathological spectrum and outcomes of crescentic glomerulonephritis (CrGN) in adult Indian population. This prospective study was done to evaluate the etiology, clinicohistological patterns and predictors of outcome of CrGN in South Indian population. All the patients received standard protocol based immunosuppression in addition to supportive care. Immune-complex glomerulonephritis (ICGN) was the most common etiology (n = 31; 77.5%) followed by pauci-immune glomerulonephritis (PauciGN; n = 8; 20%) and anti-glomerular basement membrane disease (n = 1; 2.5%). The most common etiology of ICGN was IgA nephropathy (n = 11; 27.5%) followed by lupus nephritis (n = 7; 17.5%) and post-infectious glomerulonephritis (PIGN) (n = 7; 17.5%). The patients with PauciGN were significantly older compared to those with ICGN (44.5 ± 15 years vs. 31.8 ± 11 years; P = 0.01). The patients with PauciGN presented with significantly higher serum creatinine (9.7 ± 4.4 vs. 6.6 ± 3.3 mg/dl; P = 0.03). The histopathologic parameters of ICGN and PauciGN were comparable except for a higher proportion of sclerosed glomeruli in ICGN. At the end of 3 months follow-up, only two patients went into complete remission (5.4%). Majority of the patients had end-stage renal failure (48.6%) and were dialysis dependent and seven patients (18.9%) expired. There was no signifi difference in the renal survival (10.9 ± 1.9 vs. 9.6 ± 3.3 months) or patient survival (17.5 ± 2.1 vs. 17.3 ± 4.3 months). The parameters associated with adverse outcomes at 3 months were hypertension (odds ratio [OR]: 0.58; confidence interval [CI]: 0.36-0.94), need for renal replacement therapy (OR: 0.19; CI: 0.04-0.9), serum creatinine at admission (P = 0.019), estimated glomerular filtration rate (P = 0.022) and percentage of fibrocellular crescents (P = 0.022).

We examined the capacity of mouse glomerular mesangial cells (MC) to express and function through two different low affinity FcgammaRs, the activating FcgammaRIII and the inhibitory FcgammaRII. Immunohistochemistry identified FcgammaRII as the prominent FcgammaR in the kidney, and low levels of FcgammaRIIb2-specific mRNA were also detected in primary cultures of growth-arrested MC. Activation by tumor necrosis factor-alpha/interleukin-1beta induced substantial FcgammaRII expression in proliferating MC. Importantly, however, stimulation with interferon-gamma (IFN-gamma)/lipopolysaccharide or IFN-gamma alone resulted in a complete down-regulation of FcgammaRII, which was accompanied by a strong increase in FcRgamma chain mRNA and a surface appearance of FcgammaRIII. Activating FcgammaRIII triggered mRNA synthesis for monocyte chemoattractant protein-1 (MCP-1), MCP-5, cytokine-induced neutrophil chemoattractant, and RANTES, whereas FcgammaRIII-deficient MC failed to respond to immune complex (IC) activation as shown by impaired production of MCP-1 mRNA/protein. In a passive model of acute anti-glomerular basement membrane (GBM) nephritis, induction of FcgammaRIII and suppression of FcgammaRII occurred in kidney tissues. Blockade of FcgammaRII, when induced selectively in the kidney, resulted in enhanced inflammation. Taken together, our results define a novel regulatory pathway with opposite regulation of FcgammaRII (suppressed) and FcgammaRIII (induced) by IFN-gamma on MCs in vitro and anti-GBM IgG in vivo. Herein is provided the first evidence that glomerular FcgammaRII plays an important immunoregulatory role in the initiation of IC glomerulonephritis.

In the present paper we studied the role of nitric oxide radicals (NO) on platelet aggregation, fibrinogen deposition, superoxide formation, peroxynitrite formation, hemodynamics, and leukocyte migration in the Thy-1 model of glomerulonephritis. To first study the baseline kinetics of these parameters, groups of anti-Thy-l-treated rats were sacrificed at 1 h, 4 h, 24 h, 3 days, 7 days, and 14 days and compared to controls. Urinary protein excretion was significantly elevated in Thy-1 nephritis at 3 and 7 days. Glomerular macrophages, PMNs, and superoxide anion-positive cells were significantly increased in Thy-1 nephritis. Nitrotyrosine immunoreactivity was absent during the entire study period. Glomerular platelet aggregation was significantly increased in anti-Thy-1 injected rats at 1 h, 4 h, 24 h, and 3 days. Glomerular fibrinogen deposition was significantly elevated at all time points. To elucidate the role of NO in this process, additional groups of anti-Thy-l-injected rats were treated with the NOS inhibitor L-NAME and studied at 24 h. Urinary protein excretion was significantly higher in L-NAME treated Thy-1 rats compared to nontreated Thy-1 rats. Plasma and urine nitrite/nitrate levels were significantly lower in L-NAME-treated Thy-1 rats compared to nontreated Thy-1 rats. Compared to nontreated Thy-1 rats, there were no differences in intraglomerular leukocyte accumulation after treatment with L-NAME. In contrast, we observed a marked increase in platelet aggregation following L-NAME treatment. From these data we conclude that the inflammatory infiltrate in Thy-1 nephritis develops independent of NO radical production, whereas NO radicals prevent the accumulation of platelet aggregates. (C) 2001 Elsevier Science.

Nitric oxide radicals are recognized as important mediators in various physiological and pathophysiological processes. During inflammation, increased amounts of nitric oxide (NO) are produced, but it is unclear whether NO radicals are either protective or harmful. To obtain more insight into the role of NO in glomerular inflammation, we studied the temporal expression of endothelial NO synthase (eNOS) and inducible NOS (iNOS) in conjunction with platelet aggregation, inflammatory cell influx, superoxide anion production cells, and nitrotyrosine formation in an experimental model of anti-myeloperoxidase (MPO) associated necrotizing crescentic glomerulonephritis (NCGN). Brown Norway rats were immunized with MPO in complete Freund's adjuvant (CFA) or CFA alone. After two weeks, the left kidney was perfused with a neutrophil lysosomal extract and H2O2. Rats were sacrificed at 24 hours, four days, and 10 days after perfusion. Kidney sections were stained by immunohistochemistry for eNOS, iNOS, platelets, nitrotyrosines, polymorphonuclear cells (PMN), monocytes, and T-cells. Superoxide anion producing cells were identified by enzyme cytochemistry using diaminobenzidine. Strong staining for eNOS was found in glomerular capillaries and interstitial tubular capillaries and larger vessels from non-perfused kidneys. At 24 hours after perfusion, glomerular and interstitial eNOS staining was greatly reduced, which was associated with massive platelet aggregation. At later time points, eNOS expression was absent in severely damaged glomeruli. Inducible NOS expression was found at all time points in infiltrating inflammatory cells, which by double labeling studies were identified as PMNs and monocytes. The peak in iNOS expression was observed at four days after perfusion but declined thereafter. Superoxide anion and nitrotyrosine generating cells were also found at all time points, bur were most abundantly present at four days after perfusion, coinciding with the peak in iNOS expression. Double labeling experiments revealed that most nitrotyrosine generating cells also produced superoxide anions and expressed iNOS. In conclusion, these studies suggest that during the course of anti-MPO associated NCGN, loss of NO production by eNOS in conjunction with NO radical production by iNOS contribute to tissue injury. This is compatible with a protective role for eNOS contrasting with the possibly harmful effects of iNOS in anti-MPO associated NCGN.

SummaryMyeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing crescentic glomerulonephritis (NCGN) is characterized by abundant leucocyte infiltration. Chemokines are chemotactic cytokines involved in receptor-mediated recruitment of leucocytes. Our objective was to analyse spatiotemporal gene expression of chemokines and chemokine receptors in anti-MPO-mediated NCGN, to find potential targets for intervening with leucocyte influx. NCGN was induced in mice by co-administration of anti-MPO immunoglobulin (Ig)G and lipopolysaccharide. mRNA expression levels of chemokines and chemokine receptors were analysed in whole kidney lysates as well as in laser microdissected glomeruli and tubulo-interstitial tissue 1 and 7 day(s) after NCGN induction. Several chemokines and chemokine receptors were induced or up-regulated in anti-MPO-mediated NCGN, both on day 1 (chemokines CCL3, 5; CXCL2, 5, 13; receptor CXCR2) and on day 7 (chemokines CCL2, 5, 7, 8, 17, 20; CXCL1, 2, 5, 10; CX3CL1; receptors CCR2, 8; CX3CR1). The expression levels of most chemokines and receptors were higher in glomeruli than in the tubulo-interstitium. Because of the temporal induction of CXCR2 on day 1, we hypothesized CXCR2 as a potential target for treatment in anti-MPO-induced NCGN. Inhibition of CXCR2 using a goat-anti-CXCR2 serum prior to NCGN induction increased glomerular neutrophil influx but did not affect crescent formation and albuminuria. In conclusion, expression levels of various chemokines and chemokine receptors were increased in anti-MPO NCGN, and expressed particularly in glomeruli. These chemokines and receptors may serve as potential targets for treatment. Inhibition of a single target, CXCR2, did not attenuate anti-MPO NCGN. Combinatorial interventions may be necessary to avoid redundancy.

P>What are the molecular mechanisms of bacterial infections triggering or modulating lupus nephritis? In nephritic MRLlpr/lpr mice, transient exposure to bacterial cell wall components such as lipopeptide or lipopolysaccharide (LPS) increased splenomegaly, the production of DNA autoantibodies, and serum interleukin (IL)-6, IL-12 and tumour necrosis factor (TNF) levels, and aggravated lupus nephritis. Remarkably, bacterial lipopeptide induced massive albuminuria in nephritic but not in non-nephritic mice. This was associated with down-regulation of renal nephrin mRNA and redistribution from its normal localization at foot processes to the perinuclear podocyte area in nephritic MRLlpr/lpr mice. Bacterial lipopeptide activates Toll-like receptor 2 (TLR2), which we found to be expressed on cultured podocytes and glomerular endothelial cells. TNF and interferon (IFN)-gamma induced TLR2 mRNA and receptor expression in both cell types. Albumin permeability was significantly increased in cultured podocytes and glomerular endothelial cells upon stimulation by bacterial lipopeptide. LPS also induced moderate albuminuria. In summary, bacterial lipopeptide and LPS can aggravate glomerulonephritis but only lipopeptide potently induces severe albuminuria in MRLlpr/lpr mice. EU Integrated Project INNOCHEM (FP6-518167) DeutscheForschungsgemeinschaft (AN372/8-1,GRK1202) Else Kröner-Fresenius Stiftung and the Deutsche Fors-chungsgemeinschaft (SE888/4-1)

Induction of microhematuria by an IgA isotype switch variant of a monoclonal anti-Thy-1. 1 antibody in the rat. IgA nephropathy (IgAN) is a chronic form of glomerulonephritis (GN) characterized by the deposition in the glomerular mesangium of mainly IgA. An experimental form of mesangial proliferative GN can be induced in rats by either polyclonal or monoclonal antibodies against Thy-1.1, a glycoprotein present on the surface of MC. The IgG-mcdiatcd renal inflammation is complement dependent and associated with influx of platelets and monocytes. In the present study we switched an IgG2a anti-Thy-1.1 (ER4G) producing hybridoma to an IgA anti-Thy-1.1 (ER4A) producing clone and analyzed the effects of IgA anti-Thy-1.1 in rats. FPLC analysis by gel filtration revealed that the IgA produced by the hybridoma cells was mainly dimeric and polymeric. Infusion of rats with purified ER4A (1 mg/kg) resulted in the deposition of IgA in a mcsangiai pattern in the glomeruli, similar to that found with ER4G. While administration of ER4G resulted in proteinuria, no significant urinary protein excretion was found in rats treated with ER4A. However, significant microhematuria was observed in rats receiving either ER4A or ER4G. Furthermore, the administration of ER4A was not accompanied by activation of complement, and no significant influx of monocytes or polymorphonuclear leukocytes was observed in contrast to the rats receiving ER4G. We conclude that microhematuria is selectively induced in Wistar rats by mouse IgA anti-Thy-1.1 without detectable complement-mediated injury to MC. These studies may be of importance in understanding the mechanisms leading to IgAN in patients.

Expression of iNOS, eNOS and peroxynitrite-modified proteins in experimental anti-MPO associated necrotizing crescentic glomerulonephritis. Nitric oxide radicals are recognized as important mediators in various physiological and pathophysiological processes. During inflammation, increased amounts of nitric oxide (NO) are produced, but it is unclear whether NO radicals are either protective or harmful. To obtain more insight into the role of NO in glomerular inflammation, we studied the temporal expression of endothelial NO synthase (eNOS) and inducible NOS (iNOS) in conjunction with platelet aggregation, inflammatory cell influx, superoxide anion production cells, and nitrotyrosine formation in an experimental model of anti-myeloperoxidase (MPO) associated necrotizing crescentic glomerulonephritis (NCGN). Brown Norway rats were immunized with MPO in complete Freund's adjuvant (CFA) or CFA alone. After two weeks, the left kidney was perfused with a neutrophil lysosomal extract and H 2 O 2 . Rats were sacrificed at 24 hours, four days, and 10 days after perfusion. Kidney sections were stained by immunohistochemistry for eNOS, iNOS, platelets, nitrotyrosines, polymorphonuclear cells (PMN), monocytes, and T-cells. Superoxide anion producing cells were identified by enzyme cytochemistry using diaminobenzidine. Strong staining for eNOS was found in glomerular capillaries and interstitial tubular capillaries and larger vessels from non-perfused kidneys. At 24 hours after perfusion, glomerular and interstitial eNOS staining was greatly reduced, which was associated with massive platelet aggregation. At later time points, eNOS expression was absent in severely damaged glomeruli. Inducible NOS expression was found at all time points in infiltrating inflammatory cells, which by double labeling studies were identified as PMNs and monocytes. The peak in iNOS expression was observed at four days after perfusion but declined thereafter. Superoxide anion and nitrotyrosine generating cells were also found at all time points, but were most abundantly present at four days after perfusion, coinciding with the peak in iNOS expression. Double labeling experiments revealed that most nitrotyrosine generating cells also produced superoxide anions and expressed iNOS. In conclusion, these studies suggest that during the course of anti-MPO associated NCGN, loss of NO production by eNOS in conjunction with NO radical production by iNOS contribute to tissue injury. This is compatible with a protective role for eNOS contrasting with the possibly harmful effects of iNOS in anti-MPO associated NCGN.