BRIEF REVIEW www.jasn.org Idiopathic Retroperitoneal Fibrosis Augusto Vaglio and Federica Maritati Nephrology Unit, University Hospital, Parma, Italy ABSTRACT Idiopathic retroperitoneal fibrosis (RPF), reviewed herein, is a rare fibro-inflammatory emerged: IgG4‑RD embraces fibro- disease that develops around the abdominal aorta and the iliac arteries, and spreads inflammatory disorders affecting differ- into the adjacent retroperitoneum, where it frequently causes ureteral obstruction and ent structures (e.g., pancreas, biliary renal failure. The clinical phenotype of RPF is complex, because it can be associated tract, lymph nodes) and is characterized with fibro-inflammatory disorders involving other organs, is considered part of the by lympho-plasmacytic inflammation, spectrum of IgG4-related disease, and often arises in patients with other autoimmune irregular and pronounced fibrosis, and conditions. Obstructive uropathy is the most common complication, although other infiltration by IgG4+ plasma cells. Idio- types of renal involvement may occur, including stenosis of the renal arteries and veins, pathic RPF belongs to this disease spec- renal atrophy, and different types of associated GN. Environmental and genetic factors trum.11,12 Finally, idiopathic RPF may be contribute to disease susceptibility, whereas the immunopathogenesis of RPF is me- associated with systemic (e.g., small- diated by different immune cell types that eventually promote fibroblast activation. vessel vasculitis, rheumatoid arthritis) The diagnosis is made on the basis of computed tomography or magnetic resonance and organ-specific(e.g., Hashimoto thy- imaging, and positron emission tomography is a useful tool in disease staging and roiditis) autoimmune diseases, which follow-up. Treatment of idiopathic RPF aims at relieving ureteral obstruction and in- makes the puzzle of its nosology even ducing disease regression, and includes the use of glucocorticoids, combined or not more complex.1 with other traditional immunosuppressants. However, biologic therapies such as the Bcell–depleting agent rituximab are emerging as potentially efficacious agents in difficult-to-treat cases. PATHOLOGY J Am Soc Nephrol 27: ccc–ccc, 2016. doi: 10.1681/ASN.2015101110 Idiopathic RPF is a fibro-inflammatory disease, histologically hallmarked by fi- brous tissue and chronic inflammation. The term retroperitoneal fibrosis (RPF) topography. The disease usually involves The fibrous tissue comprises an extracel- is used to describe a condition of variable the adventitia of the abdominal aorta lular matrix composed of type I collagen etiology characterized by a highly fibrotic and the iliac arteries and the surround- fibers organized in thick irregular bundles retroperitoneal mass that frequently ing retroperitoneum, and histologically and often encircling small retroperitoneal causes ureteral obstruction. RPF encom- shows a mixture of fibrous tissue and vessels (Figure 1). Fibroblasts show signs passes the idiopathic form (.75% of the chronic inflammation.6 In addition, it of activation and transition into myofibro- cases) and secondary forms, which in- also frequently affects the thoracic blasts (a‑smooth muscle actin expres- clude cases secondary to malignancies, aorta.7 For these reasons, the term sion), and are probably the major source infections, drugs, radiotherapy, or other “chronic periaortitis,” coined in the of collagen production.6 They rarely show conditions.1,2 1980s, seems to be more appropriate. mitoses, although they have been shown to Idiopathic RPF is a rare disease, with Chronic periaortitis also includes in- undergo clonal proliferation.13 an estimated incidence of 0.1–1.3 cases/ flammatory abdominal aortic aneu- 100,000 persons per year, and a preva- rysms (without ureteral involvement) fi Published online ahead of print. Publication date lence of 1.4 cases/100,000 inhabi- and perianeurysmal brosis (with ure- available at www.jasn.org. tants.2,3 The male-to-female ratio is teral involvement); the two latter condi- 2:1–3:1, and the mean age at onset tions are clinically and histologically Correspondence: Dr. Augusto Vaglio, Unità Oper- ativa di Nefrologia, Azienda Ospedaliero-Universitaria 4,5 ranges between 55 and 60 years. Al- similar to idiopathic RPF except for aor- di Parma, Via Gramsci 14, 43126 Parma, Italy. Email: though RPF has become the most used tic aneurysmal dilatation.8–10 [email protected] nameforthisdisease,itdoesnotade- During the last decade, the concept of Copyright © 2016 by the American Society of quately reflect its pathology or its exact IgG4-related disease (IgG4‑RD) has Nephrology J Am Soc Nephrol 27: ccc–ccc, 2016 ISSN : 1046-6673/2707-ccc 1 BRIEF REVIEW www.jasn.org The inflammatory infiltrate consists are also found. They are identified using vascular territories; thoracic aorta in- of numerous lymphocytes, plasma cells, tryptase immunostaining, which also volvement can be seen in both IgG4+ – and macrophages. Neutrophil infiltra- demonstrates their degranulating state, and IgG4 cases.7 tion is rare, and so are granulomas. The a finding consistent with their active inflammatory cells are interspersed participation in the fibro-inflammatory within the collagen bundles (“diffuse” reaction.16 CLINICAL MANIFESTATIONS AND pattern), but are also organized in nod- The aforementioned lesions involve LABORATORY FINDINGS ular aggregates, usually around small not only the periaortic retroperitoneum, vessels. Such aggregates have a B cell but also the aortic wall. In typical cases Clinical Signs and Symptoms core surrounded by T cells, which are with periaortic RPF distribution, the Systemic symptoms (e.g., fatigue, an- predominantly CD4+.Insomecases, fibro-inflammatory reaction mainly in- orexia, weight loss), possible expression these lymphoid follicles have the struc- volves the aortic adventitia, whereas the of an inflammatory status, often herald ture of germinal centers (Figure 1), other aortic layers may show atheroscle- the disease onset (Table 1). They usually which reveals ectopic lymphoneo- rotic changes; this is the basic notion coexist with back, flank, or abdomi- genesis, a process typical of chronic behind the concept of chronic periaorti- nal pain. Pain is usually dull, does autoimmune diseases.6,14 Plasma cells ac- tis, which was initially described as not modify with position, and tran- count for a significant proportion of the an exaggerated fibro-inflammatory, siently responds to nonsteroidal anti- inflammatory cells, and when the IgG4+/ adventitial, and peri-adventitial reac- inflammatory drugs; in cases of ureteral total IgG+ plasma cell ratio is .40%, tion to atherosclerotic plaque com- involvement, it may mimic a ureteral co- RPF is classified as “IgG4-related” if ponents.9,17,18 Such aortic wall lesions lic. Constipation may be another dis- other features such as storiform fibrosis, may also occur in the thoracic aorta and ease-related manifestation, although it eosinophil infiltration, and obliterative its major branches in patients whose is rarely severe. Other urologic manifes- phlebitis are also present.11,15 Mast cells periaortitis extends to involve these tations are frequent: they range from testicular pain, often accompanied by hydrocele and/or varicocele– due to spermatic vein encasement by RPF– to retrograde ejaculation and erectile dys- function. Other less common manifes- tations include frequency, hematuria, and dysuria.2,4,5,19 Ureteral and Renal Complications Ureteral involvement is the most com- mon disease-related complication; the disease usually causes medial ureteral deviation, and frequently obstruction of the pelvic ureteral tract.20 This is why RPF limited to the periaortic space rarely causes ureteral obstruction, whereas RPF with peri-iliac extension frequently does. Ureteral encasement can be unilat- eral or bilateral, and in the latter case ARF is frequent; in cases with unilateral involvement, contralateral progression can occur weeks to years after the initial presentation.4,5 An interesting finding at Figure 1. Histopathology of idiopathic RPF. (A) Low-power magnification view of a diagnosis is renal hypoplasia/atrophy fi retroperitoneal biopsy showing abundant and irregular brosis replacing normal retro- (diameter ,8.5 cm), at a frequency of fl fi peritoneal soft tissues (asterisk), and an in ammatory in ltrate organized in a lymphoid 8%–30% (Table 1). Whether this is due aggregate that is centered around a small retroperitoneal artery (arrow). (B) A lymphoid to previous ureteral obstruction, renal 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 dif- artery stenosis by RPF, or other causes, fusely interspersed within collagen bundles. (D) These collagen bundles form rinds is still unclear. Indeed, idiopathic RPF around small retroperitoneal vessels (arrows). Hematoxylin and eosin (A–D). Original can extend to the renal vascular pedun- magnification, 34inA(baris0.5mm);310 in B (bar is 300 mm); 320 in C and D (bar is cle:10 this may cause compression of 300 mm). renal veins (which is often slowly 2 Journal of the American Society of Nephrology J Am Soc Nephrol 27: ccc–ccc,2016 www.jasn.org BRIEF REVIEW Table 1. Main demographic, clinical and laboratory findings of patients with idiopathic RPF in four different clinical series Johns Hopkins A. Schweitzer University Mayo Clinic, University, Hospital, Hospital, Rochester Baltimore Dordrecht Parma (n=185)4 (n=48)19 (n=53)2 (n=210) Mean age at diagnosis,