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In humans cryoglobulinemic glomerulonephritis (CGGN) may develop in the course of systemic cryoglobulinemia (CG) and is often associated with hepatitis C virus infection. It is believed that the glomerular injury in CG results from the deposition of immune complexes, but exact sequence of events in this process is unknown. Experimental models of CGGN provide an important tool to study pathogenesis of this type injury. This review describes two mouse models of CGGN and their use in understanding the role of various molecules involved in regulation of inflammatory and fibrosis pathways, such as complement components, Fc receptors, growth factors, and others; as well as illustrates their role in testing novel approaches of treatment in this type of renal injury.

Blockade of the renin-angiotensin system is renoprotective in a variety of chronic nephropathies, but the direct effect of such treatment in active, immune complex-mediated glomerulonephritis is unknown. This study investigated the short- and long-term effects of an angiotensin-converting enzyme inhibitor (enalapril) and an angiotensin II type 1 receptor blocker (losartan) in thymic stromal lymphopoietin transgenic (TSLPtg) mice, which develop mixed cryoglobulinemia and severe cryoglobulinemia-associated membranoproliferative glomerulonephritis. Enalapril and losartan each reduced hypertension, proteinuria, glomerular extracellular matrix deposition, and mesangial cell activation in TSLPtg mice. These renoprotective effects were not observed with hydralazine treatment, despite a similar antihypertensive effect. Treatment with enalapril or losartan also decreased renal plasminogen activator inhibitor-1 in TSLPtg mice, assessed by immunohistochemistry and quantitative real-time reverse transcriptase-PCR. None of the treatments affected immune complex deposition or macrophage infiltration. Overall, enalapril- and losartan-treated TSLPtg mice survived significantly longer than untreated TSLPtg mice. These studies demonstrate that angiotensin blockade may provide renoprotective benefits, independent of its BP-lowering effect, in the treatment of active immune complex-mediated glomerulonephritis.

Fibrillary glomerulonephritis is a now widely recognized diagnostic entity, occurring in approximately 1% of native kidney biopsies in several large biopsy series obtained from Western countries. The distinctive features are infiltration of glomerular structures by randomly arranged fibrils similar in appearance but larger than amyloid fibrils and the lack of staining with histochemical dyes typically reactive with amyloid. It is widely but not universally recognized to be distinct from immunotactoid glomerulopathy, an entity characterized by glomerular deposits of immunoglobulin with substructural organization as microtubules and with clinical associations with lymphoplasmacytic disorders. The pathophysiologic basis for organization of the glomerular deposits as fibrils or microtubules in these entities remains obscure.

Unlabelled: Cyclophosphamide is a cytostatic drug, widely used in therapy of secondary glomerulonephritis. Because pulse therapy bears less side effects than oral one we aimed to follow the cyclophosphamide effect on the course of patients with primary glomerulonephritis. We observed 20 pts (7 women and 13 men), mean age 33 +/- 10.0 yrs, age range 18-50 yrs with primary glomerulonephritis and proteinuria more than 3.5 g. 12 patients also had erythro-cyturia. In all pts kidney biopsy was performed, but in one woman the biopsy was not diagnostic. Renal biopsy revealed: FSG in 2 pts, membranous glomerulonephritis in 2 pts, in 9 pts mesangial proliferative changes and in 6--mesangiocapillary lesions. In 5 pts renal failure was observed. Cyclophosphamide was administered i.v. in the dose 0.75 g/m2 b.s., no more than 1.0 g per dose, in renal failure 0.5 g/m2. During the first six months patients received cyclophosphamide every month and then every three months. Before cyclophosphamide pulse therapy all patients were pretreated with steroids, 3 pulses of 1.0 g Methylprednisolone and then oral prednisone in the dose 20 mg/m2 body surface., Results: In 3 patients we obtained remission of proteinuria, in 11 patients decrease of proteinuria but 6 patients didn't answer to the introduced treatment. In whole group of examined patients we obtained the statistically significant decrease of proteinuria from 12.2 +/- 10.5 to 5.3 +/- 5.2 g (p < 0.05) after the treatment. The creatinine clearance did not change in the time of the treatment and any special complications during the treatment were observed. We suggest that cyclophosphamide pulse therapy could be an effective treatment in pts with primary glomerulonephritis. Our results showed that the answer of proposed treatment was independent of the type to the changes found in kidney biopsy.

Purpose: Cryoglobulinemic glomerulonephritis (CGGN) is a type of membranoproliferative glomerulonephritis (MPGN) that develops in patients with systemic cryoglobulinemia. To date the exact pathogenesis of CGGN remains unclear. It has been suggested that macrophages may be significant contributors to the glomerular injury in this disease. In our study we attempt to characterize the macrophages in human CGGN using classical activation and regulatory macrophage markers. Material and Method: We searched our database for renal biopsy cases of CGGN. Macrophages were detected using a monoclonal anti-CD68 antibody. Two groups of macrophage markers were used: classical activation markers, including iNOS, CXCL9 and CCL20, and regulatory markers: SPHK1 and LIGHT. The stains were performed using immunohistochemical method. Results: Five patients with CGGN were identified. Four patients had systemic cryoglobulinemia and two had a serological evidence of hepatitis C virus infection. In all cases the glomeruli contained numerous macrophages. Staining for activatory macrophage markers revealed a strong nuclear staining for CXCL9 in numerous cells, including those corresponding to the macrophage location. Staining for the other activatory markers, as well as staining for regulatory markers, was not significant. Conclusion: In this study of human CGGN we showed a striking expression of cytokine CXCL9, a classical macrophage activation marker, by the macrophages and possibly other cell types within the glomeruli. This observation points to the possible role of classically activated macrophages in the pathogenesis of MPGN. If this observation is confirmed on a larger group of patients, the cytokine CXCL9 could become a potential therapeutic target for human CGGN. [ABSTRACT FROM AUTHOR]