Idiopathic Retroperitoneal Fibrosis

Abstract

Idiopathic retroperitoneal fibrosis (RPF), reviewed herein, is a rare fibro-inflammatory disease that develops around the abdominal aorta and the iliac arteries, and spreads into the adjacent retroperitoneum, where it frequently causes ureteral obstruction and renal failure. The clinical phenotype of RPF is complex, because it can be associated with fibro-inflammatory disorders involving other organs, is considered part of the spectrum of IgG4-related disease, and often arises in patients with other autoimmune conditions. Obstructive uropathy is the most common complication, although other types of renal involvement may occur, including stenosis of the renal arteries and veins, renal atrophy, and different types of associated GN. Environmental and genetic factors contribute to disease susceptibility, whereas the immunopathogenesis of RPF is mediated by different immune cell types that eventually promote fibroblast activation. The diagnosis is made on the basis of computed tomography or magnetic resonance imaging, and positron emission tomography is a useful tool in disease staging and follow-up. Treatment of idiopathic RPF aims at relieving ureteral obstruction and inducing disease regression, and includes the use of glucocorticoids, combined or not with other traditional immunosuppressants. However, biologic therapies such as the B cell-depleting agent rituximab are emerging as potentially efficacious agents in difficult-to-treat cases.

Keywords: IgG4; fibrosis; hydronephrosis; retroperitoneal fibrosis; vasculitis.

Figure 1.

Histopathology of idiopathic RPF. (A) Low-power magnification view of a retroperitoneal biopsy showing abundant and irregular fibrosis replacing normal retroperitoneal soft tissues (asterisk), and an inflammatory infiltrate organized in a lymphoid aggregate that is centered around a small retroperitoneal artery (arrow). (B) A lymphoid nodular aggregate with a clear (germinal) center (arrow) is visible. (C) Diffuse pattern of the inflammatory infiltrate, mainly consisting of lymphocytes and plasma cells that are diffusely interspersed within collagen bundles. (D) These collagen bundles form rinds around small retroperitoneal vessels (arrows). Hematoxylin and eosin (A–D). Original magnification, ×4 in A (bar is 0.5 mm); ×10 in B (bar is 300 μm); ×20 in C and D (bar is 300 μm).

Figure 2.

Immunopathogenetic mechanisms of idiopathic RPF. Susceptibility to idiopathic RPF is conferred by exposure to environmental agents (asbestos, smoking) and by genetic factors such as HLA class II alleles (HLA‑DRB1*03). The presence of a restricted HLA class II repertoire makes it likely that the disease is antigen-driven, although the triggering antigens are as yet unknown. Antigen-presenting cells present such hypothetical antigens to CD4⁺ cells within the aortic wall or the surrounding retroperitoneum. CD4⁺ T cells expand, secrete IL‑6, which is able to activate B cells and fibroblasts. CD4⁺ T cells also secrete Th2 cytokines such as IL‑4, IL‑10 and IL‑13, which drive B-cell expansion and maturation into plasma cells, and may lead to preferential expansion of IgG4-producing plasma cells. Lymphoid cells also secrete eotaxin‑1, which drives recruitment of eosinophils and mast cells, whose products are also able to activate fibroblasts. Once activated, fibroblasts mature into myofibroblasts and secrete collagen. This pathogenetic hypothesis and the resulting cartoon have been generated on the basis of the available evidence on the immunopathogenetic mechanisms of the disease. See text for further details.

Figure 3.

Computed tomography findings in idiopathic RPF. (A, B) Typical idiopathic RPF that develops around the anterior and lateral sides of the abdominal aorta (A, arrow) and both common iliac arteries (B, arrow). (C) A rare complication of idiopathic RPF, that is a perirenal urinoma (asterisk) due to severe right-hand ureteral obstruction; the arrow indicates the periaortic tissue. (D) In a patient with periaortic (white arrow) and peri-iliac (not shown) RPF, marked hypoplasia of the right kidney (black arrow) as well as severe left-hand hydronephrosis. Indwelling ureteral stents can be seen bilaterally in the renal pelvis. (E) Typical case of perianeurysmal RPF, where the periaortic tissue surrounds an aneurysmal aorta (left-hand arrow) and causes hydronephrosis of the left kidney (arrow), which appears atrophic. Endovascular aorto-iliac prosthesis can be seen in the aortic lumen. (F) Periaortic idiopathic RPF encasing the origin of both renal arteries (arrows).

Figure 4.

PET findings in idiopathic RPF. ¹⁸F‑FDG PET scans in a patient with idiopathic RPF show intense accumulation of ¹⁸F‑FDG around the abdominal aorta (arrows) (A, sagittal view, B, coronal view).

Figure 5.

Proposed therapeutic algorithm for idiopathic RPF. IS, immunosuppressants (particularly mycophenolate mofetil, methotrexate, azathioprine, cyclophosphamide); RTX, rituximab; TCZ, tocilizumab.