Modulation of antibody-mediated glomerular injury in vivo by interleukin-6

Modulation of antibody-mediated glomerular injury in vivo by interleukin-6. We have shown previously that pretreatment with small doses of bacterial lipopolysaccharide (LPS), human recombinant interleu-kin-1β (hrIL-1β) and human recombinant tumor necrosis factor-α (hrTNF) increase injury in the heterologous phase of nephrotoxic nephritis (NTN). All three pretreatments induce synthesis of interleukin-6 (IL-6) which in some systems down-regulates synthesis of IL-1 and TNF. We have now investigated the influence of IL-6 on injury in both heterologous and autologous phases of NTN in rats. Injection of hrIL-6 in doses sufficient to induce hepatic synthesis of acute phase proteins (assessed by plasma α2-macroglobulin concentration) had no effect on glomerular injury in the heterologous phase of NTN (albuminuria in NTAb alone 9 ± 6; LPS/NTAb 34 ± 10 and IL-6/NTAb 2 ± 1 mg/24 hr, P < 0.001, Wilcoxon test). In contrast, IL-6 pretreatment partially abrogated the effect of LPS on albumin excretion (NTAb 4 ± 2; LPS/NTAb 85 ± 11 and IL-6/LPS/NTAb 32 ± 6 mg/24 hr, P < 0.002), percentage of glomerular capillary thrombi (3 ± 1%; 39 ± 8%; and 6 ± 1%, P < 0.001) and glomerular neutrophil infiltrate (29 ± 3; 58 ± 5; and 34 ± 2 neutrophils/50 glomeruli in section, P < 0.001, respectively) at 24 hours. The effect of IL-6 was also evident four hours after induction of nephritis and was associated with a marked reduction in glomerular concentration of mRNA for IL-1β and TNF, without change in that of tubulin. Serum TNF concentrations were also significantly reduced at four hours in IL-6 treated rats. Glomerular macrophage counts were unaffected by the treatment of IL-6 at four (53 ± 1; 55 ± 3 and 64 ± 7) or 24 hours (201 ± 12; 198 ± 9 and 202 ± 9, respectively). A single injection of IL-6 also decreased albumin excretion by 42% in the autologous phase of NTN, and reduced the prevalence of glomerular capillary thrombosis by 68%. These results show that IL-6 has significant anti-inflammatory properties in this model of antibody mediated injury in vivo

Differential expression of macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 in experimental glomerulonephritis

Differential expression of macrophage inflammatory protein-2 and monocyte chemoattractant protein-1 in experimental glomerulonephritis. We examined the relation between glomerular expression of chemokines from α-subfamily (macrophage inflammatory protein-2, MIP-2) and β-subfamily (monocyte chemoattractant protein-1, MCP-1) and infiltration of neutrophils and monocytes in antibody mediated glomerulonephritis in rats. In the accelerated model of nephrotoxic nephritis (NTN), glomerular expression of MIP-2 and MCP-1 genes correlated with the sequential migration of neutrophil and monocyte influx, respectively. These relationships were investigated further in the heterologous phase of NTN by applying various treatments known to modulate the severity of injury. Pretreatment with bacterial lipopolysaccharide resulted in greater injury, MIP-2 expression increased 25- to 50-fold, and the glomerular neutrophil count increased two- to fourfold. Both MIP-2 mRNA levels and neutrophil infiltration were reduced by additional pretreatment with IL-6, IL-1 receptor antagonist, soluble IL-1 receptor or soluble TNF receptor (Spearman correlation coefficient r = 0.897, P < 0.005). In the heterologous phase of NTN, different pre-treatments only resulted in trivial changes in MCP-1 expression and monocyte infiltration. In conclusion, glomerular MIP-2 gene expression correlates with neutrophil infiltration both temporally during the evolution of nephritis, and when glomerular injury is modified by treatment. Glomerular MCP-1 gene expression correlates with monocyte influx. The data show chemokines of α- and β-subfamilies co-operative to cause selective and sequential migration of different leukocyte subsets during development of antibody mediated glomerulonephritis

Rituximab as a rescue therapy in patients with glomerulonephritis

To evaluate the use of rituximab in the treatment of severe glomerulonephritis (GN) in order to prevent progression of kidney disease toward the end stage, we designed a multicenter, retrospective study in Saudi Arabia about the efficacy and safety of the use of "off label" rituximab in a variety of severe refractory GN to conventional treatment and the progression of kidney disease for at least one year of follow-up. All the patients had kidney biopsies before treatment with rituximab, and proteinuria and glomerular filtration rate (GFR) were followed-up for the period of the study. The immediate side-effect at the time of administration of rituximab included itching in three patients, hypotension in one patient and anaphylaxis in one patient (dropped out from the study). After the administration of rituximab in 42 patients and during the first six months of therapy, 16 (38%) patients had complete remission (CR), 13 (31%) patients had partial remission (PR) and 13 (31%) patients had no remission. The mean follow-up period for the patients was 19.0 ± 6.97 months (median 18.0 months). The long-term follow-up during the study period disclosed a good hospitalization record for almost all of the patients. Membranous GN (MGN) was the largest group in the cohort (58% of the patients), and we observed CR and PR in 40% and 28% of them, respectively, which was comparable with the previous experience with rituximab in MGN patients with more CR than PR in our cohort. We conclude that our study suggests the safety and efficacy of the use of rituximab in patients with refractory GN and that larger and long-term prospective studies are required to define the role of rituximab in the different categories of these diseases