Mononuclear cell activation and decreased renal function in IgA nephropathy with crescents

Abstract

Our previous immunohistologic studies with monoclonal antibodies (mAb) showed that glomerular and interstitial accumulations of mononuclear cells (MNC) were common features of many types of proliferative glomerulonephritis, especially crescentic glomerulonephritis. The current study examined a series of patients with crescentic IgA disease, since IgA disease in general has a highly variable course and the presence of crescents is one indicator of likely progression to end-stage renal failure. We compared the intraglomerular and interstitial infiltrates within biopsies from patients with crescentic IgA nephropathy (N = 5) versus those with noncrescentic IgA (N = 18), or normal controls (N = 10). Few leucocytes were found within glomeruli of normal (2.4 ± 0.7 cells/glomerular cross section) (mean ± SEM) or noncrescentic IgA disease biopsies (3.8 ± 0.7), and no activated MNC bearing receptors for interleukin-2 (IL-2R) were detected. By contrast, in crescentic IgA disease, glomerular leucocytes were increased (5.1 ± 0.6, P<0.01), due to increased monocyte (3.1 ± 0.9, P<0.01) and T cell (1.4 ± 0.4, P<0.01) infiltration, and IL-2R+MNC were then observed (1.2 ± 0.5, P<0.05). Studies of interstitial cells showed small numbers of leucocytes within normal kidneys (101 ± 16/mm2). Biopsies from noncrescentic IgA disease showed a fivefold increase in interstitial MNC infiltration (total leucocytes 565 ± 105/mm2, P<0.01), due to an influx of T cells (283 ± 59/mm2, P<0.01) and monocytes (120 ± 32/mm2, P<0.01), and including a mean of 20% IL-2R+MNC (114 ± 29/mm2, P<0.01). This picture of dramatically increased interstitial MNC infiltration in IgA disease was further amplified in IgA disease with crescent formation, when total leucocytes reached 784 ± 153/mm2 (P<0.01 vs. normals), due to large numbers of monocytes (376 ± 83/m2, P<0.01 vs. normals or noncrescentic cases) and T cells (423 ± 99, P<0.01 vs. normals). In addition, crescentic biopsies contained even more IL-2R+ cells (44%) than noncrescentic IgA biopsies (348 ± 96/mm2, P<0.05 vs. noncrescentic IgA). The numbers of interstitial total leucocytes (P<0.05), monocytes (P<0.05), T cells (P<0.01) and IL-2R+ (P<0.01) cells were all positively correlated with raised serum creatinine, and were negatively correlated with creatinine clearance. Since IL-2 plays a central role in T cell activation, and MNC expression of IL-2R is a closely regulated event, these studies suggest that local cellular immune activation is involved in the immunopathogenesis of IgA nephropathy, particularly in cases featuring crescent formation.