Idiopathic Retroperitoneal Fibrosis

BRIEF REVIEW www.jasn.org

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 fibrous 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

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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 manifestations include frequency, hematuria, and dysuria.2,4,5,19

Ureteral and Renal Complications Ureteral involvement is the most common 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 unilateral 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

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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, years 58 54 64 58 Male gender, % 61 54 77 70 Systemic symptoms, %a 27 60 92 66 Pain (flank, abdominal), % 38 94 92 81 Testicular manifestations 13 27 46 51 (pain, varicocele, hydrocele), % Constipation, % 12 NA 30 28 Lower extremity edema, % 13 23 8 15 Lower extremity claudication, % 2 NA 11 12 Hydronephrosis, % 57 67 55 72 Unilateral, % 25 21 40 29 Bilateral, % 32 46 15 43 Renal atrophy, % 8 NA 21 30 Impaired renal function, %b 42 NA 66 57 Mean ESR, mm/h 32 40 45 63 Mean CRP, mg/L 20.7 NA 23 32 Mean serum creatinine, mg/dL 1.3 NA 1.4 3.9c Mean Hb, g/dL 12.6 11.6 12.4 12.5 Increased ESR, % 53 NA 74 85 Increased CRP, % 47 NA 62 78 NA, not available; ESR, erythrocyte sedimentation rate; CRP, C‑reactive protein; Hb, hemoglobin. Normal CRP values are ,5mg/L. The series included in this table were selected essentially on the basis of their sample size and the accuracy of data reporting. In the first series (Mayo Clinic) data were collected retrospectively, whereas in the remaining series they were collected prospectively. Data included in the Parma series are unpublished. For testicular manifestations, the percentage was calculated on male patients only. aSystemic symptoms include: fatigue, anorexia, weight loss and low-grade fever. bImpaired renal function indicates a serum creatinine level .1.2 mg/dL. cIn this series, the distribution of serum creatinine was not normal, therefore we also report median (range) serum creatinine levels, which are 1.4 (0.5–23) mg/dL. progressive and allows the formation of may contribute. Again, probably due to activity. Although high baseline acute- collateral circles),21 and renal arteries the slow progression of venous encase- phase reactants are associated with a with resulting reno-vascular hyperten- ment, collateral circles develop, there- more symptomatic disease, these param- sion. New-onset hypertension or wors- fore inferior vena cava syndrome, deep eters poorly predict response to therapy ening of preexisting hypertension is vein thrombosis, and pulmonary embo- and do not correlate with mass regres- found in up to one-third of patients at lism are uncommon.4,19,23 sion.25,26 Additionally, relapses com- diagnosis.19 Other vascular districts may also be monly occur when acute-phase reactants involved. The periaortic tissue can ex- are still normal.27 Serum IL‑6isalso Vascular Complications tend to the mesenteric and celiac arteries, high, reflecting an acute-phase response; Aneurysmal forms of RPF must be care- causing stenosis and ischemic complica- its correlation with disease activity or fully followed for timely repair of the tions resembling mesenteric vasculitis.24 prognosisisunexplored.28 High IgG4 aortic aneurysm; interestingly, both sur- Up to one-third of patients with abdom- levels have been linked to IgG4-related gical and endovascular repair have been inalRPFalsohavethoracicaortain- RPF, but a systematic assessment of IgG4 associated with regression of perianeur- volvement, most of them presenting in idiopathic RPF is lacking. However, ysmal RPF, although RPF may also de- with thoracic aorta aneurysm, the pro- the exact proportion of patients with velop following endovascular treatment gression of which must also be carefully high serum IgG4, as well as the prognos- of atherosclerotic aortic aneurysms.22 monitored.7 tic significance of this biomarker are still Idiopathic RPF typically arises around unknown. Experimental studies on the aorta and iliac arteries, but stenosis Laboratory Findings small cohorts showed that serum che- of these vessels is quite rare.2,4 Con- Acute-phase reactants such as erythro- mokinessuchaschemokine(C-Cmo- versely, venous compression (mainly of cyte sedimentation rate and C‑reactive tif) ligand 11 (CCL11)/eotaxin‑116 and the inferior vena cava) is common, and protein levels are increased in the major- CCL1829 are increased during active dis- can cause lower limb edema, to whose ity of patients at presentation and are ease; CCL18 correlates with RPF thick- pathogenesis lymphatic compression routinely used to monitor disease ness variations after therapy.29

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ASSOCIATION WITH showed typical Hashimoto thyroiditis or involving other structures, especially scle- AUTOIMMUNE OR FIBRO- its fibrous variant.30 However, cases of rosing pancreato-cholangitis, fibrosing INFLAMMATORY DISEASES Riedel thyroiditis were also described.31 mediastinitis, orbital pseudotumor, and Other associations include rheumatoid sclerosing sialoadenitis; this multiorgan One intriguing aspect of idiopathic RPF is arthritis,32 ankylosing spondylitis,33 disorderwasoncereferredtoasmulti- its associationwithautoimmune disorders, ANCA-associated vasculitis,34–36 systemic focal fibrosclerosis.46 The recognition which highlights the pathogenic relevance lupus erythematosus,37 and psoriasis.38 of a shared histopathologic background of autoimmune mechanisms. Autoimmune Idiopathic RPF has also been linked to between these lesions– with main fea- thyroiditis is the most frequently associated different types of GN, particularly mem- tures being irregular (“storiform”) fibro- autoimmune condition: in a recent case– branous nephropathy (MN).39,40 This as- sis, lymphoplasmacytic infiltrates and control study, idiopathic RPF patients sociation is interesting, because MN is an abundance of IgG4+ plasma cells– pro- had a prevalence of anti-thyroperoxidase IgG4-mediated disease;41 however, target vided the rationale for their inclusion in antibodies of 24.7% (versus 10.6% in antigens in MN associated with RPF or the spectrum of IgG4‑RD.47 Recent stud- healthy controls) and ultrasound evidence IgG4‑RD probably differ from those (e.g., ies have demonstrated that, based on of thyroiditis; after a median follow-up phospholipase A2 receptor) detected in histologic findings (e.g., IgG4+ plasma of 45 months, 25% of RPF patients de- classic MN.39,42–45 cell infiltration), #50%ofidiopathic veloped hypothyroidism requiring Idiopathic RPFcan alsobe associated RPF can be histologically classified as L‑thyroxine. Where available, histology with fibro-inflammatory conditions “IgG4-related” even when the disease is

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.

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antigens would be presented by plaque macrophages to lymphoid cells resid- ing in the adventitia, where they would elicit a fibro-inflammatory response.8,9,17,18 This theory, however, cannot explain the complex clinical spectrum of idiopathic RPF, particularly the associations with autoimmune or fibro-inflammatory diseases involving other organs. Additionally, the disease can develop in patients without atherosclerotic lesions or involve vascular territories spared by atherosclerosis.7,10 These findings raised the question whether idiopathic RPF is a manifestation of a systemic condition rather than a localized reaction to atherosclerosis. The pathogenesis of the disease is multifactorial. Environmental agents play a definite role: an association with asbestos exposure has been postulated, and anecdotal cases of pleural asbestosis in RPF patients have been described.3,49 Arecentcase–control study confirmed the predisposing role of asbestos exposure and also identified smoking as a risk factor. Interestingly, smoking and asbestos had a multiplicative effect on disease risk, with an odds ratio of 12.04 (95% confidence interval, 4.32 to 38.28) in 23 Figure 3. Computed tomography findings in idiopathic RPF. (A, B) Typical idiopathic RPF co-exposed subjects. The role of other that develops around the anterior and lateral sides of the abdominal aorta (A, arrow) and environmental or infectious agents re- both common iliac arteries (B, arrow). (C) A rare complication of idiopathic RPF, that is a mains elusive. Genetic determinants perirenal urinoma (asterisk) due to severe right-hand ureteral obstruction; the arrow indi- also contribute to disease susceptibility. cates the periaortic tissue. (D) In a patient with periaortic (white arrow) and peri-iliac (not Idiopathic RPF is associated with shown) RPF, marked hypoplasia of the right kidney (black arrow) as well as severe left-hand HLA‑DRB1*03, a risk factor for other hydronephrosis. Indwelling ureteral stents can be seen bilaterally in the renal pelvis. (E) autoimmune diseases such as lupus er- Typical case of perianeurysmal RPF, where the periaortic tissue surrounds an aneurysmal ythematosus and type 1 diabetes.50 aorta (left-hand arrow) and causes hydronephrosis of the left kidney (arrow), which appears Other genetic associations include the atrophic. Endovascular aorto-iliac prosthesis can be seen in the aortic lumen. (F) Periaortic D32 polymorphism of the gene encoding idiopathic RPF encasing the origin of both renal arteries (arrows). CCR5, a chemokine receptor,51 and the TTCCAT haplotype of the gene encod- not associated with other IgG4RD le- disease spectrum. Additionally, how of- ing CCL11/eotaxin‑1.16 sions;11,15 however, systematic analyses ten RPF overlaps with other IgG4‑RD CD4+ T cells are abundant in idio- of large cohorts are lacking. IgG4-re- manifestations is still unclear. pathic RPF biopsies;6 in IgG4‑RD lesions lated and -unrelated RPF do not appear they show a T-helper 2 (Th2)-polarization to differ clinically, except for a higher and produce IL‑4, IL‑5, and IL‑13, frequency of extra-retroperitoneal man- PATHOGENESIS although regulatory T cells are also ifestations in the former group; in par- found.52 In idiopathic RPF, it has been ticular, they have similar demographic Idiopathic RPF,as part of the spectrum of shown that T cells also locally produce and laboratory characteristics, compa- chronic periaortitis, was initially viewed IL‑6, which can activate B cells and fi- rable mass location and thickness, and as a localized reaction to antigens con- broblasts. B lymphocytes account for a almost identical rates of ureteral in- tained in the atherosclerotic plaques of high proportion of infiltrating cells and volvement.11 Therefore, it is likely that the abdominal aorta such as oxidized may be precursors of plasma cells; Th2 they represent different ends of the same low-density lipoproteins.48 Such cytokines may induce the enrichment of

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low in T1-weighted images and variable (high in active stages) in T2-weighted images. Contrast enhancement and diffusion coefficient values are useful in dif- ferentiating active and inactive lesions.56 When RPF has a bulky appearance, in- homogeneous intensity on MRI, extends above the origin of the renal arteries, or tends to displace the aorta anteriorly, it is more likely to be malignant. Also, malignant RPF causes medial ureteral deviation less frequently than idiopathic RPF.57 18F‑Fluorodeoxyglucose (18F‑FDG) positron emission tomography (PET) hasemergedasausefultoolforthe assessment of RPF activity (Figure 4);27,58,59 this technique also detects the metabolic activity of post-treatment residual disease and thus guides subse- quent therapy.60 Notably, 18F‑FDG PET allows whole-body imaging and can help identify extra-retroperitoneal lesions to which RPF may be associated (e.g., thoracic periaortitis, IgG4‑RD) or secondary lesions (e.g., malignancies).7,61 However, 18F‑FDG PET has little diag- Figure 4. PET findings in idiopathic RPF. 18F‑FDG PET scans in a patient with idiopathic nostic utility because many infectious, RPF show intense accumulation of 18F‑FDG around the abdominal aorta (arrows) (A, sagittal inflammatory, or neoplastic lesions also view, B, coronal view). accumulate 18F‑FDG. Although no guidelines exist, retro- the IgG4+ plasma cell subset, although proteins, tryptase) stimulate fibroblast peritoneal biopsy is usually performed this has not yet been proven in RPF.47 proliferation and collagen produc- (via open, laparoscopic, or CT-guided The pathogenic importance of the IL‑6– tion.16 Fibroblasts can also be activated approaches) in cases with atypical mediated axis and of B cells was con- by CCL18, a chemokine whose serum localization (e.g., periureteral, perire- firmed in vivo by the efficacy of therapies levels are increased in idiopathic RPF.29 nal),54,62,63 or with clinical or imaging targeting the IL‑6 receptor (tocilizu- The immunopathogenesis of idiopathic findings consistent with neoplastic mab)28 and the B cell marker CD20 (rit- RPFissummarizedinFigure2. RPF.57 The percentage of biopsy-proven uximab),53 but it must be acknowledged cases varies widely among series, with a that these data are limited to small case range of 24%–77%.4,5,64 series. Th2 responses are often character- DIAGNOSIS ized by tissue eosinophilia, which is also Differential Diagnosis observed in idiopathic RPF and Imaging Studies and Role of Biopsy Malignancies and infections are the major IgG4‑RD. Tissue recruitment of eosino- Idiopathic RPF is usually diagnosed by challenges for the diagnosis of RPF. Ma- phils can be driven by chemokines such computed tomography (CT) or mag- lignancies that can mimic RPF on CT/MRI as CCL11/eotaxin‑1, whose tissue ex- netic resonance imaging(MRI).On CT, include retroperitoneal lymphomas and pression and serum levels are high in id- itappearsasahomogeneousplaque sarcomas, and retroperitoneal metastases iopathic RPF. Eotaxin‑1alsoinduces surrounding the anterolateral sides of from various types of carcinomas.54,55 recruitment of mast cells, which have the abdominal aorta and encircling the Carcinoids can cause RPF– through as been found in idiopathic RPF lesions. common iliac arteries (Figure 3); medial yet unclear mechanisms– even without Notably, in idiopathic RPF biopsies, eo- ureteral deviation and/or obstruction metastasizing to the retroperitoneum.65 sinophils and mast cells strongly ex- andinferiorvenacavaencasementare Among infections, tuberculosis should al- press CCR3, the receptor for CCL11/ common. The tissue is muscle-isodense ways be considered: it can spread into the eotaxin‑1.16 Eosinophil and mast cell and has varying degrees of contrast en- retroperitoneum from neighboring foci products (e.g., eosinophil granule hancement.54,55 On MRI, its intensity is or be disease-triggering when located

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Figure 5. Proposed therapeutic algorithm for idiopathic RPF. IS, immunosuppressants (particularly mycophenolate mofetil, methotrexate, azathioprine, cyclophosphamide); RTX, rituximab; TCZ, tocilizumab. distantly.66 Pelvic actinomycosis may TREATMENT AND OUTCOME per day of prednisone gradually tapered to mimic pelvic RPF and should be suspected 5–7.5 mg/day within 6–9 months.5,72 particularly in women with a history of The first goal of treatment is the relief of Remission generally indicates symptom intrauterine device use.67 ureteral obstruction. Surgical ureteroly- and hydronephrosis resolution, together RPF has traditionally been linked to sis with intraperitonealization and with acute-phase reactant normalization the use of drugs, particularly ergot alka- omental wrapping of the ureters is no and radiographic regression. Remission loids (e.g., methysergide, ergotamine) longer the first-line approach, and con- rates after steroid therapy range between and dopamine agonists (e.g., pergolide); servative procedures (e.g., double-J stent 75% and 95%;5,72 mean mass thickness intriguingly, recent reports described or nephrostomy placement) followed by reduction is around 50%.5 Glucocorti- RPF developing during anti-TNFa ther- medical therapy are preferred.70 Ureteral coids are rapidly effective, and most of apy for rheumatoid arthritis.68 Radio- stenting allows better quality of life than the radiographic response is seen in the therapy, major abdominal surgery, and does nephrostomy and is usually suc- first weeks of treatment. However, they trauma are uncommon causes of RPF. cessful; however, stents and nephrosto- can also fail to induce mass regression, RPFalsodevelopsinErdheim–Chester mies have comparable complication and chronic residual hydronephrosis disease, a non-Langerhans histiocytosis rates (e.g., infection, obstruction).71 Al- may require surgical ureterolysis. that – unlike idiopathic RPF – tends though no guidelines exist, when ure- Tamoxifen, an anti-estrogen agent to infiltrate the perirenal space.69 Fi- teral obstruction is mild and there is no with potential antifibrotic activity, has nally, Takayasu and giant-cell arteritis kidney function impairment, it seems been proposed as an alternative to glu- cancausediffuseaorticthickening advisable to start medical therapy with- cocorticoids73 particularly in patients and thus mimic RPF, but they lack ret- out urinary drainage. experiencing steroid-related toxicity or roperitoneal diffusion and ureteral Glucocorticoids are the first-line ther- when there are contraindications to glu- involvement.7 apy, with initial doses of 0.75–1mg/kg cocorticoids.64,74 However, in a recent

J Am Soc Nephrol 27: ccc–ccc, 2016 Retroperitoneal Fibrosis 7 BRIEF REVIEW www.jasn.org randomized controlled trial, an 8‑month renal outcomes. Studies with long-term 2. van Bommel EF, Jansen I, Hendriksz TR, fi treatment with tamoxifen was signifi- follow-up (median, 48–61 months) Aarnoudse AL: Idiopathic retroperitoneal - – brosis: prospective evaluation of incidence cantly less effective than a treatment provide mortality rates of 3.3% and clinicoradiologic presentation. Medicine 4,5 with prednisone of equal duration in 7.3%. Varying degrees of chronic renal (Baltimore) 88: 193–201, 2009 maintaining remission in patients treat- insufficiency occur in up to 32% of the 3. Uibu T, Oksa P, Auvinen A, Honkanen E, ed with prednisone induction (1 mg/kg patients,4 but end-stage renal disease is Metsärinne K, Saha H, Uitti J, Roto P: As- per day for 1 month).5 Therefore, to exceedingly rare. bestos exposure as a risk factor for retroper- fi itoneal fibrosis. Lancet 363: 1422–1426, date, the ef cacy of tamoxifen is not sup- 2004 ported by controlled trials and its supe- 4. Kermani TA, Crowson CS, Achenbach SJ, riority to other agents is unproven. CONCLUSIONS Luthra HS: Idiopathic retroperitoneal fibro- Immunosuppressants have been used sis: a retrospective review of clinical pre- in combination with glucocorticoids; how- Idiopathic RPF is an idiopathic disease that sentation, treatment, and outcomes. Mayo Clin Proc 86: 297–303, 2011 ever, it is still debated whether they actually sits in the spectrum of fibro-inflammatory fi 5. Vaglio A, Palmisano A, Alberici F, Maggiore potentiate glucocorticoid ef cacy or func- disorders and should be viewed as a po- U, Ferretti S, Cobelli R, Ferrozzi F, Corradi D, tion as steroid-sparing agents. Mycophe- tentially systemic condition. Genetic and Salvarani C, Buzio C: Prednisone versus ta- nolate mofetil is widely used, also given its environmental agents confer disease sus- moxifen in patients with idiopathic retroper- ceptibility and represent active areas of itoneal fibrosis: an open-label randomised good tolerability and lack of contraindi- – research. Immune-mediated and autoim- controlled trial. Lancet 378: 338 346, 2011 cationsinpatientswithrenalinsuffi- 6. Corradi D, Maestri R, Palmisano A, Bosio S, 75,76 ciency. Cyclophosphamide has also mune mechanisms play relevant patho- Greco P, Manenti L, Ferretti S, Cobelli R, been effectively used as initial therapy genic roles; new therapies targeting specific Moroni G, Dei Tos AP, Buzio C, Vaglio A: followed by maintenance with other im- pathways will complement traditional im- Idiopathic retroperitoneal fibrosis: clinico- munosuppressants, but is currently not munosuppressive approaches. pathologic features and differential diagnosis. Kidney Int 72: 742–753, 2007 fi 77,78 recommended as rst-line therapy. 7. Palmisano A, Urban ML, Corradi D, Cobelli R, The patients who achieve remission Alberici F, Maritati F, Versari A, Pipitone N, must be carefully followed using labora- ACKNOWLEDGMENTS Salvarani C, Buzio C, Vaglio A: Chronic peri- tory examinations, periodic ultrasound aortitis with thoracic aorta and epiaortic ar- (to monitor hydronephrosis and aneu- tery involvement: a systemic large vessel We are indebted to all of our colleagues that vasculitis? Rheumatology (Oxford) 54: 2004– rysmal dilatation) and CT/MRI studies contribute to the clinical management and 2009, 2015 (able to accurately define size and mor- research on RPF. In particular, we would like 8. Parums DV: The spectrum of chronic peri- phologic changes of RPF) to allow early aortitis. Histopathology 16: 423–431, 1990 to thank Alessandra Palmisano, Maria Letizia detection of relapses. Long-term main- 9. Parums DV, Chadwick DR, Mitchinson MJ: Urban, and Lucio Manentifor their help in the tenance therapy must be considered, The localisation of immunoglobulin in care of RPF patients, Stefania Ferretti for her chronic periaortitis. Atherosclerosis 61: 117– particularly in patients with aggressive role in the management of urologic compli- 123, 1986 disease. Idiopathic RPF is indeed a cations of RPF patients, Maria Nicastro and 10. Vaglio A, Pipitone N, Salvarani C: Chronic chronic-relapsing disorder, with relapse periaortitis: a large-vessel vasculitis? Curr Domenico Corradi for their support with rates of up to 72%.72 Importantly, re- Opin Rheumatol 23: 1–6, 2011 histopathologic analysis and for providing his- lapsing patients often experience multi- 11. Khosroshahi A, Carruthers MN, Stone JH, tologic figures, Mary Pavia for contributing Shinagare S, Sainani N, Hasserjian RP, ple relapses and are thus exposed to high to data collection, Davide Martorana and Deshpande V: Rethinking Ormond’sdisease: cumulative glucocorticoid doses. In such “ ” fi Francesco Bonatti for performing genetic idiopathic retroperitoneal brosis in the cases, methotrexate has been success- era of IgG4-related disease. Medicine (Bal- studies, Annibale Versari and Rocco Cobelli fully used as a steroid-sparing agent.79 timore) 92: 82–91, 2013 for imaging studies, Carlo Salvarani, Giacomo Figure 5 shows a proposed therapeutic 12. Mahajan VS, Mattoo H, Deshpande V, Pillai Emmi, and Nicolò Pipitone for their helpful SS, Stone JH: IgG4-related disease. Annu algorithm for idiopathic RPF. clinical insights. A special thanks goes to our Rev Pathol 9: 315–347, 2014 Although rare, refractory cases also former chief Carlo Buzio, who initiated and 13. 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