Clinical Investigation
Therapeutic Mechanism of Glucocorticoids on Cellular Crescent Formation in Patients With Antiglomerular Basement Membrane Disease☆,☆,☆☆

https://doi.org/10.1016/j.amjms.2017.04.015Get rights and content

Abstract

Background

This study aimed to explore the therapeutic mechanism of glucocorticoids (GCs) in antiglomerular basement membrane disease.

Materials and Methods

Thirty-four patients with biopsy-proven antiglomerular basement membrane nephritis were divided into the following 2 groups: group 1 (patients treated with GCs, n = 22) and group 2 (patients who were not treated with GCs, n = 12). The expression of parietal epithelial cells (PECs), activated PECs and glucocorticoid receptors (GRs) was examined quantitatively and compared between the 2 groups. Correlations between GR expression in glomeruli and patients’ clinicopathological indices were also analyzed.

Results

Compared with patients in group 2, patients in group 1 showed lower levels of serum creatinine (SCr) (P = 0.03), average cellular crescent percentage (P = 0.005) and macrophages infiltrating in renal interstitium (P = 0.03). PECs (P = 0.007) and activated PECs (P = 0.03) were strongly detected in the cellular components of classic crescents, and both were significantly reduced in group 1 compared to group 2. GR expression either in glomeruli (P = 0.01) or interstitium (P = 0.009) was lower in group 1 after GCs treatment than in group 2. Additionally, GR expression in glomeruli was strongly correlated with renal function (SCr: r = 0.45, P = 0.009; eGFR: r = −0.35, P = 0.046), the proportion of cellular crescents (r = 0.67, P < 0.001), PECs (r = 0.64, P < 0.001) and activated PECs (r = 0.72, P < 0.001), and the degree of interstitial (r = 0.50, P = 0.004) and glomerular (r = 0.49, P = 0.007) macrophage infiltration.

Conclusions

GCs might exert their therapeutic effects via inhibiting the activation and proliferation of PECs, as well as macrophage infiltration, which could contribute to crescent formation and determine renal survival. GRs are involved in this process as well.

Introduction

Glomerular crescents, as multilayered proliferating cells in Bowman’s space, usually imply a poor prognosis and represent a pivotal determinant of glomerular fate in rapidly progressive glomerulonephritis (RPGN). In both human and experimental crescentic glomerulonephritis, glomerular epithelial cells have been observed to be predominant in crescents when Bowman’s capsule is intact. However, inflammatory cells and fibroblasts have been found to play a more significant role after the rupture of Bowman’s capsule.1, 2, 3, 4 Although the origins of cellular crescents have been controversial for a long time, growing evidence has revealed that crescents are likely to derive from the activation and proliferation of parietal epithelial cells (PECs) by detecting PEC markers in the crescent cells of all types of glomerulonephritis.5, 6, 7, 8 Therefore, PECs might be of critical importance in the formation and development of crescentic glomerulonephritis.

Crescentic glomerulonephritis, a disease of significant morbidity and mortality, has an incidence of 1.56% in renal biopsies from a 10-year period in our center.9 Currently, glucocorticoids (GCs), induced as pulsed intravenous therapy and maintained by oral treatment, are still the standard therapy in the clinic.10, 11 It has been clinically demonstrated that clinical and histological abnormalities could be ameliorated by GCs therapy. Additionally, the therapy is still effective after the development of disease and diffuse crescent formation. GCs exert their pharmacologic effects by binding to glucocorticoid receptors (GRs). Researches have shown that GRs are highly expressed in the nuclei of PECs and moderately detected in the cytoplasm.12 Furthermore, GR expression has also been observed in inflammatory cells, such as monocytes, macrophages and lymphoid cells. Therefore, it could be presumed that either the injured glomerular cells or inflammatory cells derived from peripheral blood could be the target cells of GCs in crescentic glomerulonephritis.

Antiglomerular basement membrane (GBM) nephritis, a common type of crescentic glomerulonephritis, is an autoimmune disorder characterized by RPGN. This study investigated the changes in GR expression in renal tissues of patients with anti-GBM nephritis after GCs treatment. PECs and activated PECs were also evaluated. This study aimed to analyze the correlations between GR expression and patients’ clinicopathological features, and explore the mechanism by which GCs therapy could ameliorate clinical and histological abnormalities. This study also aimed to find out whether this mechanism is associated with the regulating of the proliferation and activation of PECs.

Section snippets

Patients

All patients were enrolled in Jinling Hospital (Nanjing, China) from January 2003 through October 2013. A total of 34 patients with biopsy-proven anti-GBM nephritis were recruited. Clinicopathological parameters were obtained from the electronic medical record system. The patients were divided into the following 2 groups: group 1 was treated with GCs before renal biopsy (n = 22) and group 2 was treated without GCs (n = 12). All patients received supportive and symptomatic treatments without

General Conditions and Clinicopathological Features

There were 15 (44.1%) females and 19 (55.9%) males, with an average age of 40.9 ± 17.4 years, and the duration of anti-GBM nephritis in patients was 4 weeks (interquartile range: 3-9). All patients showed RPGN, and more than half (61.8%) of the cases were accompanied by gross hematuria. Most of the patients (84.2%) had hypertension. The differences in general conditions and clinicopathological characteristics between the 2 groups were analyzed. Patients in group 1 exhibited a lower level of SCr

Discussion

Crescentic glomerulonephritis, the most severe form of glomerular pathologies, is histologically characterized by extracapillary proliferation in ≥50% of glomeruli. An irreversible loss of renal function may occur within days to several months. Thus, early diagnosis and treatment are necessary. Clinically, high-dose GCs therapy is used as a common and standard approach. However, the therapeutic benefit of GCs on cell-mediated immunity or glomerular cells is not well known in crescentic

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    ☆

    First and second authors contributed equally to this work.

    ☆

    The authors have no conflicts of interest to disclose.

    ☆☆

    This work was supported by Jiangsu Province basic research project of Natural Science Foundation (BK20131327) and National Natural Science Foundation of China, China (81400722).

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