Contribution of cellular infiltration to the progression of IgA nephropathy: A longitudinal, immunocytochemical study on repeated renal biopsy specimens

Abstract

A retrospective immunocytochemical study was performed on repeated renal biopsy specimens from 47 patients with IgA nephropathy, 23 of whom received steroid therapy after the initial biopsy. Immune cells in renal tissues were detected by the immunoperoxidase method using monoclonal antibodies against common leukocyte antigens, T cells, B cells and monocytes/macrophages.Overall, glomerular infiltration of total leukocytes and monocytes/macrophages was significantly correlated with proteinuria. Interstitial infiltration of total leukocytes, T cells and monocytes/macrophages was significantly correlated with histological injury and renal dysfunction. In the steroid-treated group (group S), urinary protein and glomerular infiltration of total leukocytes and macrophages were significantly reduced at the follow-up biopsy, while these parameters remained unchanged in the nonsteroid-treated group (group N). In group S, interstitial infiltration of almost all of the various cell types, histological renal damage and renal function remained unchanged at the follow-up biopsy, while group N showed a significant increase in the number of interstitial total leukocytes, T cells and macrophages and showed a significant progression of histological renal injury.These findings suggest that glomerular immune cells, especially monocytes/macrophages, are involved in inducing proteinuria and interstitial immune cells are involved in renal deterioration. Furthermore, steroid therapy appears to reduce urinary protein and prevent the progression of tissue injury through suppression of renal infiltration of these inflammatory cells.

Macrophage-Mediated Renal Injury Is Dependent on Signaling via the JNK Pathway

“…The density of macrophage accumulation correlates with the degree of renal dysfunction and is predictive of disease progression (2)(3)(4)(5), suggesting that macrophages mediate acute and progressive renal injury. Similarly, many temporal studies in both immune and non-immune-initiated models of kidney disease have shown a clear association between macrophage accumulation and the development of renal injury (reviewed by Nikolic-Paterson et al [2]).…”

Interferon-γ Augments Acute Macrophage-Mediated Renal Injury Via a Glucocorticoid-Sensitive Mechanism

“…These cells have been implicated in causing renal injury on the basis that their accumulation correlates with renal dysfunction (2), and the density of macrophage infiltration is predictive of disease progression in IgA nephropathy and lupus nephritis (3,4). A pathogenic role for macrophages in causing renal injury is supported by timecourse studies in which renal macrophage accumulation parallels the progression of renal injury (5).…”

In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interactions

“…In IgAN, T cells, monocytes, and macrophages are the predominant infiltrating mononuclear cells in the tubulointerstitium (1,5,26,32). IgAN patients with increased infiltration of CD25ϩ cells in the tubulointerstitium are often associated with deteriorating renal function (17,25).…”

“…Of note, experiments conducted with IgA from MpIgAN patients induced a greater transmigration of monocytes, with or without CD25 expression, compared with other studied groups. Tubulointerstitial infiltration of monocytes correlates with tubular injury and renal dysfunction in glomerulonephritis, including IgAN, through different mechanisms (16,28,31,32). Structural tubular damage and extracellular matrix deposition occur following the release of fibrogenic growth factors, proteolytic enzymes, and oxygen radicals from activated monocytes (11).…”

“…The average time to ESRD was 3.5 Ϯ 2.7 yr for patients with marked tubular atrophy in renal biopsies, in contrast to 8 -10 yr for those without (14). A consistent feature of tubulointerstitial inflammation is the presence of infiltrating mononuclear leukocytes, with predominantly T cells, monocytes, and macrophages, which play an important role in the progression of tubular injury and renal fibrosis (1,5,17,32,40). Proximal tubular epithelial cells (PTEC) secrete multiple chemokines to recruit inflammatory cells to the interstitium (6,35,41).…”