TO041
CCR2 ANTAGONISM REDUCES PROTEINURIA AND GLOMERULAR INJURY IN MURINE MODELS OF FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)

INTRODUCTION AND AIMS: Focal segmental glomerulosclerosis (FSGS) comprises a group of uncommon disorders that present with marked proteinuria, nephrotic syndrome, progressive renal failure and characteristic glomerular lesions on histopathology. The current standard of care includes renin-angiotensin-aldosterone blockade and trials of moderate to high dose corticosteroids and/or immunosuppresants. Despite best care, treatment failure is common, and FSGS is causal in at least 4% of patients with end stage renal disease. Several lines of evidence support a role for chemokine receptor 2 (CCR2) positive monocyte/macrophages in the pathogenesis of FSGS, and inhibition of CCR2 presents a potential therapeutic treatment of FSGS.

METHODS: In this study, we have investigated the efficacy of a small molecule CCR2 antagonist in two murine models of FSGS. In the 5/6 remnant kidney model 129X1/SvJ mice underwent surgery to completely remove one kidney, and 2/3 of the remaining kidney. Beginning three weeks post-surgery they were treated once daily with a CCR2 antagonist and/or angiotensin II receptor blocker (ARB) candesartan (CST). In the second model, Adriamycin (doxorubicin) was administered intravenously (7.5 mg/kg) to Balb/c mice, who were then treated with a CCR2 antagonist and/or CST, beginning 2 hours prior to treatment of Adriamycin. Kidney injury was assessed by proteinuria (urinary albumin excretion rate, or UAER; urine albumin creatinine ratio or ACR), serum creatinine and histological readouts.

RESULTS: In the 5/6 remnant kidney model, mice had a rapid reduction in UAER when treated with either the CCR2 antagonist (77% reduction by week 2) or CST (79% reduction). Significantly, addition of the CCR2 antagonist to CST further reduced the UAER (91% reduction; p < .001 versus CST alone). The protective effects were evident within 1 week of treatment and were maintained for the duration of the study (6 weeks). The same renal protective effects of CCR2 blockade were seen in the Adriamycin nephropathy model. Administration of Adriamycin caused significant proteinuria (75 mg/day in vehicle treated group by week 1), which was significantly reduced by administration of CCR2 antagonist (65% reduction in UAER; p = .05 versus vehicle), but not by CST alone. As in the 5/6 nephrectomy model, the combination of the CCR2 antagonist and CST resulted in a synergistic protective effect (74% reduction; p = .027 versus vehicle), after two weeks of treatment. Similar results were seen when UACR was measured, and the protective effect was maintained through the end of the study (week 4). Histological parameters also improved with the combination of the CCR2 antagonist and CST; these included reduced glomerular hypertrophy, glomerular sclerosis, and mesangial expansion and increased podocyte density.

CONCLUSIONS: We conclude that blocking CCR2 provides significant and rapid renal protection in two distinct models of FSGS, as measured both by reduction in proteinuria and improvement in multiple histological parameters, and thus represents a novel and mechanistically distinct approach for the treatment of FSGS.