PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org

Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy

Charles E. Alpers and Jolanta Kowalewska

Department of Pathology, University of Washington, Seattle, Washington

ABSTRACT extracellular accumulation of haphaz- Fibrillary glomerulonephritis is a now widely recognized diagnostic entity, occur- ardly arranged fibrils measuring ap- ring in approximately 1% of native kidney biopsies in several large biopsy series proximately 16 nm in thickness. Podo- obtained from Western countries. The distinctive features are infiltration of glo- cyte foot processes were diffusely merular structures by randomly arranged fibrils similar in appearance but larger effaced. There was no evidence of than amyloid fibrils and the lack of staining with histochemical dyes typically fibrillary deposits in the tubular base- reactive with amyloid. It is widely but not universally recognized to be distinct from ment membranes or interstitium. The immunotactoid glomerulopathy, an entity characterized by glomerular deposits of diagnosis of fibrillary glomerulone- immunoglobulin with substructural organization as microtubules and with clinical phritis was established on the basis of associations with lymphoplasmacytic disorders. The pathophysiologic basis for the ultrastructural findings in conjunc- organization of the glomerular deposits as fibrils or microtubules in these entities tion with the negative Congo Red stain remains obscure. and typical histologic and immunohis-

J Am Soc Nephrol 19: 34–37, 2008. doi: 10.1681/ASN.2007070757 tochemical features.

FIBRILLARY CASE PRESENTATION remaining glomeruli revealed marked expansion of mesangial stalks and ir- GLOMERULONEPHRITIS The patient was a 48-yr-old man who regular thickening of capillary walls as Fibrillary glomerulonephritis is a morpho- had a history of hypertension, hyperlip- a result of infiltration and accumula- logically defined entity characterized by idemia, obesity, and chronic renal insuf- tion of silver negative and periodic ac- glomerular accumulations of nonbranch- ficiency and was referred for evaluation id-Schiff–positive acellular material ing, randomly arranged fibrils that are ul- of proteinuria. The patient’s history was (Figure 1). There was neither signifi- trastructurally indistinguishable from notable for a myocardial infarction 5 yr cant increase in mesangial cellularity amyloid fibrils but differ from amyloid by previously. nor basement membrane “spike” for- virtue of their larger size and lack of reac- Physical examination revealed an mation. There was a background of tivity with Congo Red and other reagents obese man with BP of 168/89 mmHg and patchy interstitial fibrosis and tubular that are histochemically reactive with amy- no other notable findings. Urinalysis re- atrophy and associated interstitial in- loid.1–4 As in our case, this diagnosis re- vealed 4ϩ protein and 2ϩ glucose and flammation. Arterial vessels showed quires electron microscopic identification rare red and white blood cells and no mild intimal sclerosis. Staining with of characteristic infiltrating fibrils within casts. A 24-h urine collection revealed 8 g the Congo Red reagent for amyloidosis glomerular structures. It has been identi- of protein. Other relevant laboratory was negative. fied in approximately 0.5 to 1.0% of native data included serum albumin of 2.8 mg/ Immunofluorescence microscopy dl, creatinine of 4.2 mg/dl, and total cho- demonstrated confluent mesangial and lesterol of 204 mg/dl. Liver function tests glomerular capillary wall staining for Published online ahead of print. Publication date were within normal limits. Serologic IgG (3ϩ) and ␬ and ␭ light chain (each available at www.jasn.org. tests for evidence of autoimmune disease trace). There was no significant stain- Correspondence: Dr. Charles E. Alpers, Depart- were not obtained. ing of the glomeruli for IgA, IgM, C3, ment of Pathology, University of Washington Med- ical Center, 1959 NE Pacific Street, Box 356100, A renal biopsy showed cortex con- C1q, fibrinogen, or albumin. Ultra- NE110, Seattle, WA 98195. Phone: 206-598-6400; taining 16 glomeruli, seven of which structural examination of two glomer- Fax: 206-598-3803; E-mail: [email protected] were completely sclerosed and three of uli revealed expansion of the mesangial Copyright © 2008 by the American Society of which were segmentally sclerosed. The stalks and capillary walls as a result of Nephrology

34 ISSN : 1046-6673/1901-34 J Am Soc Nephrol 19: 34–37, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY

gested that as many as 20% of cases may be accompanied by crescent for- mation,4,5 although this number is high in our experience and the crescents are rarely a dominant feature. Most often, the glomeruli are without prominent inflammatory cell infiltration. Essen- tial to the diagnosis, as already indi- cated, is the absence of reactivity with Figure 1. Fibrillary glomerulonephritis. (A) An involved glomerulus shows mesangial regions infiltrated and expanded by acellular material; some capillary walls are thickened Congo Red or other agents typically by infiltration of this material (PAS stain). (B) The same glomerulus stained with Jones used for the histochemical demonstra- methenamine silver demonstrates focal duplication of capillary basement membrane and tion of amyloid in tissues. Immunoflu- lack of prominent argyrophilia of the infiltrating fibrillar material, in contrast to the usual orescence findings most often reveal situation with mesangial matrix. Magnification, ϫ400. polyclonal deposits of immunoglobu- lin (Ig), typically IgG, and light chains, but a small percentage of these patients kidney biopsies in at least three large biopsy DIAGNOSIS OF FIBRILLARY have monoclonal or oligoclonal Ig dep- series reported to date.3–5 It is distinct from GLOMERULONEPHRITIS osition characterized by deposits of Ig other, much rarer processes involving dep- heavy-chain and one light-chain sub- osition of glomerular fibrils such as occur The histologic appearance of fibrillary class (e.g., ␬ light chain) but not the with fibronectin glomerulopathy and col- glomerulonephritis is somewhat hetero- other.1–3 When studied by IgG subclass lagenofibrotic glomerulopathy.6 geneous. Common histologic patterns typing sera, deposition of IgG4 and Clinically, fibrillary glomerulone- include those of a membranoprolifera- IgG1 predominates in fibrillary glo- phritis most often presents in middle- tive glomerulopathy, diffuse prolifera- merulonephritis, a finding of uncertain aged to older patients (mean age 55 to tive glomerulonephritis, mesangial pro- pathophysiologic significance.4,5 The 60 yr), although the age range is wide liferative glomerulopathy and a smaller characteristic ultrastructural finding is and this disease has rarely been re- number of cases in which the pattern and an amyloid-like process in which glo- ported in the pediatric population. Pa- distribution of the fibrillary deposits is merular structures are infiltrated by tients typically present with protein- similar to that of membranous nephrop- randomly arranged, nonbranching uria, 50% within nephrotic range. athy.5 In many cases, a pattern of infiltra- fibrils that typically measure 12 to 24 Hematuria and hypertension are also tion of glomerular structures by amor- nm in diameter, with measurements common presenting conditions (60 phous acellular material is the most most frequently being approximately and 77%, respectively, in some series).5 striking feature unaccompanied by 18 to 20 nm (Figure 2).1–4 This con- No clinical laboratory findings are spe- prominent cellular proliferation (Figure trasts with the usual fibril size in amy- cific for this condition; all of the usual 1). This material can be seen to infiltrate loid (typically reported as being be- serologies obtained for the workup of mesangial regions and peripheral capil- tween 8 and 15 nm, but with the most various forms of glomerulonephritis lary walls, although in rare cases there typical measurements being 8 to 12 are typically negative and/or normal; may be no detectable histologic alter- nm).2 Fibrils in fibrillary glomerulone- however, there was a report of several ations and the glomerular appearance phritis are often enmeshed in regions patients who had features of fibrillary may be indistinguishable from minimal- in which there is electron lucency. glomerulonephritis and concomitant change disease. Some studies have sug- Granular electron-dense deposits, sim- infection with hepatitis C virus.7 The outcome for patients with this disease is frequently poor. Progression to end-stage renal disease occurs in approx- imately half of the patients within several years of diagnosis.4,5 There are no known established therapeutic regimens for this disease, and no organized clinical trials have tested the efficacy of any proposed clinical approach.8 Several studies have Figure 2. Ultrastructural features of the fibrils of amyloid (A), fibrillary glomerulonephritis documented the recurrence of this dis- (B), and microtubules of immunotactoid glomerulopathy (C). The amyloid fibrils are ease in renal transplants, which in some randomly arranged and nonbranching. In fibrillary glomerulonephritis, the fibrils are cases has resulted in nephrotic syndrome morphologically indistinguishable from those of amyloid but thicker. Immunotactoid and/or allograft loss.1,8–10 glomerulopathy is characterized by microtubules that are hollow when viewed on end.

J Am Soc Nephrol 19: 34–37, 2008 Fibrillary Glomerulonephritis 35 PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org ilar to conventional immune deposits, to define a morphologic entity character- prompt consideration of these clinical may also be present and admixed ized by glomerular deposits of Ig orga- possibilities. among the accumulations of fibrils. nized as large microtubules.2,3,5,13,14 The Although there has been a spirited Fibrillary glomerulonephritis, as the diagnosis requires ultrastructural dem- discussion among members of the renal name suggests, is primarily a disorder in- onstration of these microtubules, which community over the issue of whether volving glomeruli. Uncommonly, the are generally but not invariably Ͼ30 nm fibrillary glomerulonephritis and immu- fibrillary deposits may also involve tubu- in diameter. When so defined, immuno- notactoid glomerulopathy are best con- lar basement membranes. There are scat- tactoid glomerulopathy is a rare entity, sidered as one entity or two, this issue of tered case reports of concomitant depo- occurring one tenth as frequently as classification seems less important than sition of fibrillary deposits in extrarenal fibrillary glomerulonephritis.4 Like the recognition that both of these entities sites such as heart and lung, but inspec- fibrillary glomerulonephritis, this entity can and should be morphologically dis- tion of published illustrations suggests to occurs in an older population, with most tinguished from amyloidosis and that the us that these reports be interpreted with reported patients Ͼ50 yr of age. Patients recognition of these morphologic pat- caution. typically present with nephrotic syn- terns can suggest important clinical dis- drome (50% in one series5) but may also ease considerations that should be evalu- have features of hematuria and renal in- ated in affected patients, such as FIBRILLARY sufficiency (five out of six patients in one cryoglobulinemia, systemic lupus, and GLOMERULONEPHRITIS VERSUS of the largest series reported to date5). perhaps hepatitis C virus infection.5,11,13 IMMUNOTACTOID Specific therapeutic approaches have not Table 1 provides key features for distin- GLOMERULOPATHY been established. Recurrent disease has guishing amyloidosis, fibrillary glomeru- been reported in renal allografts. lonephritis, and immunotactoid glo- An entity that is often considered within There are clinical features that also merulopathy. the spectrum of renal diseases as fibril- support the notion that the morphologic lary glomerulonephritis is immunotac- entity of immunotactoid glomerulopa- toid glomerulopathy. In the view of thy is best considered as a distinct clinical DIFFICULTIES IN DIAGNOSIS some, immunotactoid glomerulopathy entity. These patients have a greater pre- is a unifying term for cases of glomerular disposition to an underlying lympho- Despite the clear definitions for classic deposition of both the amyloid-like plasmacytic disorder.2,3,5,13,14 This is sup- manifestations of these entities provided fibrils described as fibrillary glomerulo- ported by immunofluorescence studies in Table 1, there are cases in which the nephritis and cases in which the glomer- on renal biopsies in which clonality (i.e., differential diagnosis of fibrillary glo- ular deposits consist of larger microtu- restriction to one light-chain subclass) of merulonephritis and immunotactoid bular structures that also fail to react with the deposits frequently can be demon- glomerulopathy poses difficult chal- histochemical stains for amyloid in tissue strated by immunofluorescence micros- lenges for the pathologist. These entities sections.11,12 These microtubular struc- copy. The characteristic organized na- can be overlooked when electron mi- tures often measure Ͼ30 nm in diameter ture of the microtubular deposits is a croscopy is not performed on a renal bi- with most reported cases having mea- feature that is also occasionally encoun- opsy; there is no other means of estab- surements ranging from 34 to 49 nm.2,3 tered in patients with cryoglobulinemia lishing this diagnosis. This is a particular We and others have taken the approach and/or systemic lupus erythematosus, problem when the infiltrating fibrils of that immunotactoid glomerulopathy is a and the morphologic findings of micro- fibrillary glomerulonephritis are con- term best used in a more restricted sense, tubular deposits in a renal biopsy should fined to subepithelial portions of the glo-

Table 1. Clinicopathologic features that distinguish fibrillary glomerulonephritis from morphologically similar immunopathologic features of fibrillary/microtubular glomerulopathies Characteristic Amyloid Fibrillary Glomerulonephritis Immunotactoid Glomerulopathy Appearance Fibrils Fibrils, rarely microtubular Microtubules Fibril/microtubule size (nm) 8 to 15 (most often 8 to 12) 12 to 24 (most often 18 to 20) Ͼ30 (most often 34 to 49) Fibril arrangement in tissues Random Random Often organized in parallel arrays Reactions with histochemical Yes No No dyes Congo Red and Thioflavin T Ig deposition Monoclonal light chains in AL Usually polyclonal, occasionally Monoclonal or oligoclonal IgG type amyloid only oligoclonal or monoclonal IgG common Association with Yes, if AL type Uncommon Common lymphoplasmacytic disorders

36 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 34–37, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY merular capillary walls, giving an appear- larly lupus membranous glomerulone- fibrillary glomerulonephritis? Am J Kidney ance of membranous glomerulopathy by phritis, and it is only by clinicopatho- Dis 19: 185–191, 1992 3. Fogo A, Quereshi N, Horn RG: Morpholog- immunofluorescence microscopy and logic correlation that the correct ical and clinical features of fibrillary glomer- thus obviating the need for ultrastruc- diagnosis of lupus nephritis may be ulonephritis versus immunotactoid glomeru- tural examination in the minds of some. achieved in these cases. lopathy. Am J Kidney Dis 22: 367–377, 1993 A second source of error is not to mea- 4. Iskandar SS, Falk RJ, Jennette JC: Clinical sure the fibrils or, just as important, not and pathologic features of fibrillary glomer- to measure them accurately with a prop- PATHOGENESIS ulonephritis. Kidney Int 42: 1401–1407, 1992 erly calibrated electron microscope. A 5. Rosenstock JL, Markowitz GS, Valeri AM, more difficult challenge is finding fibrils The pathogenesis of fibrillary glomerulo- Sacchi G, Appel GB, D’Agati VD: Fibrillary or microtubules of a measured size at the nephritis is unknown. Investigations and immunotactoid glomerulonephritis: Dis- far ends of the accepted spectrums. In into pathogenesis have been hampered tinct entities with different clinical and those uncommon cases of fibrillary glo- by the absence of an animal model. One pathologic features. Kidney Int 63: 1450– 1461, 2003 merulonephritis with smaller fibrils, clue to the pathogenesis of this disease 6. Iskandar SS, Herrera GA: Glomerulopathies there is overlap with amyloid, and in has been the immunoelectron micro- with organized deposits. Semin Diagn these circumstances, in which diagnostic scopic localizations of IgG; the comple- Pathol 19: 116–132, 2002 certainty may not be achievable, it is our ment component C3 and amyloid P 7. Markowitz GS, Cheng JT, Colvin RB, Trebbin practice to rely heavily on the results of component to individual fibrils; but not WM, D’Agati VD: Hepatitis C viral infection is associated with fibrillary glomerulonephri- Congo Red staining (or staining with labels for matrix and microfibrillar pro- tis and immunotactoid glomerulopathy. other dyes that identify amyloid, such as teins including collagen type IV, heparan J Am Soc Nephrol 9: 2244–2252, 1998 Thioflavine T) to make a diagnostic dis- sulfate proteoglycan, fibronectin, and 8. Brady HR: Fibrillary glomerulopathy. Kidney tinction. Sometimes the fibrils may have fibrillin.15 These studies provide the best Int 53: 1421–1429, 1998 an atypical ultrastructural appearance: evidence to date that the fibrils in this 9. Pronovost PH, Brady HR, Gunning ME, Es- they may be curved rather than straight, disorder are composed of Ig, although pinoza O, Rennke HG: Clinical features, pre- and some fibrils may appear “hollow” they do not conclusively prove this prop- dictors of disease progression and results of renal transplantation in fibrillary immunotac- when viewed on end. In these unusual osition because it remains possible that toid glomerulopathy. Nephrol Dial Trans- cases, it must be acknowledged that the the Ig identified is secondarily bound to a plant 11: 837–842, 1996 best judgment of the pathologist will be fibrillar protein not recognized by the 10. Samaniego M, Nadasdy GM, Laszik Z, Na- as important as published criteria in antisera used. To our knowledge, the dasdy T: Outcome of renal transplantation in reaching or excluding this diagnosis. fibrils of fibrillary glomerulonephritis fibrillary glomerulonephritis. Clin Nephrol have not been extracted from biopsy, ne- 55: 159–166, 2001 One additional consideration is the 11. Schwartz MM, Korbet SM, Lewis EJ: Immu- substructural organization of Ig depos- phrectomy, or autopsy tissues; therefore, notactoid glomerulopathy. J Am Soc Neph- its in certain systemic disorders. De- biochemical approaches to characterize rol 13: 1390–1397, 2002 posits of cryoglobulins can be microtu- the involved proteins have yet to be at- 12. Schwartz MM: Immunotactoid glomerulopa- bular and indistinguishable from those tempted. thy: The case for Occam’s razor. Am J Kid- ney Dis 22: 446–447, 1993 of immunotactoid glomerulopathy; for 13. Alpers CE: Fibrillary glomerulonephritis and this reason, cryoglobulinemia should immunotactoid glomerulopathy: Two entities, be a diagnostic consideration when- DISCLOSURES not one. Am J Kidney Dis 22: 448–451, 1993 ever such deposits are encountered. Ig None. 14. Bridoux F, Hugue V, Coldefy O, Goujon JM, deposits in lupus nephritis can demon- Bauwens M, Sechet A, Preud’Homme JL, Tou- chard G: Fibrillary glomerulonephritis and im- strate substantial organization with a munotactoid (microtubular) glomerulopathy “fingerprint” appearance that is not REFERENCES are associated with distinct immunologic fea- easily confused with fibrillary glomer- tures. Kidney Int 62: 1764–1775, 2002 ulonephritis; however, the immune de- 1. Alpers CE, Rennke HG, Hopper JJR, Biava 15. Yang GC, Nieto R, Stachura I, Gallo GR: posits in lupus nephritis can occasion- CG: Fibrillary glomerulonephritis: An entity Ultrastructural immunohistochemical local- ization of polyclonal IgG, C3, and amyloid P ally have a randomly arranged fibrillar with unusual immunofluorescence features. Kidney Int 31: 781–789, 1987 component on the congo red-negative amy- substructure indistinguishable from 2. Alpers CE: Immunotactoid (microtubular) loid-like fibrils of fibrillary glomerulopathy. fibrillary glomerulonephritis, particu- glomerulopathy: An entity distinct from Am J Pathol 141: 409–419, 1992

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