Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy
Charles E. Alpers and
Jolanta Kowalewska
Department of Pathology, University of Washington, Seattle, Washington
Correspondence: Dr. Charles E. Alpers, Department of Pathology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356100, NE110, Seattle, WA 98195. Phone: 206-598-6400; Fax: 206-598-3803; E-mail: calp{at}u.washington.edu
Fibrillary glomerulonephritis is a now widely recognized diagnosticentity, occurring in approximately 1% of native kidney biopsiesin several large biopsy series obtained from Western countries.The distinctive features are infiltration of glomerular structuresby randomly arranged fibrils similar in appearance but largerthan amyloid fibrils and the lack of staining with histochemicaldyes typically reactive with amyloid. It is widely but not universallyrecognized to be distinct from immunotactoid glomerulopathy,an entity characterized by glomerular deposits of immunoglobulinwith substructural organization as microtubules and with clinicalassociations with lymphoplasmacytic disorders. The pathophysiologicbasis for organization of the glomerular deposits as fibrilsor microtubules in these entities remains obscure.
The patient was a 48-yr-old man who had a history of hypertension,hyperlipidemia, obesity, and chronic renal insufficiency andwas referred for evaluation of proteinuria. The patient's historywas notable for a myocardial infarction 5 yr previously.
Physical examination revealed an obese man with BP of 168/89mmHg and no other notable findings. Urinalysis revealed 4+ proteinand 2+ glucose and rare red and white blood cells and no casts.A 24-h urine collection revealed 8 g of protein. Other relevantlaboratory data included serum albumin of 2.8 mg/dl, creatinineof 4.2 mg/dl, and total cholesterol of 204 mg/dl. Liver functiontests were within normal limits. Serologic tests for evidenceof autoimmune disease were not obtained.
A renal biopsy showed cortex containing 16 glomeruli, sevenof which were completely sclerosed and three of which were segmentallysclerosed. The remaining glomeruli revealed marked expansionof mesangial stalks and irregular thickening of capillary wallsas a result of infiltration and accumulation of silver negativeand periodic acid-Schiff–positive acellular material (Figure 1).There was neither significant increase in mesangial cellularitynor basement membrane "spike" formation. There was a backgroundof patchy interstitial fibrosis and tubular atrophy and associatedinterstitial inflammation. Arterial vessels showed mild intimalsclerosis. Staining with the Congo Red reagent for amyloidosiswas negative.
Figure 1. Fibrillary glomerulonephritis. (A) An involved glomerulus shows mesangial regions infiltrated and expanded by acellular material; some capillary walls are thickened by infiltration of this material (PAS stain). (B) The same glomerulus stained with Jones methenamine silver demonstrates focal duplication of capillary basement membrane and lack of prominent argyrophilia of the infiltrating fibrillar material, in contrast to the usual situation with mesangial matrix. Magnification, x400.
Immunofluorescence microscopy demonstrated confluent mesangialand glomerular capillary wall staining for IgG (3+) and and light chain (each trace). There was no significant stainingof the glomeruli for IgA, IgM, C3, C1q, fibrinogen, or albumin.Ultrastructural examination of two glomeruli revealed expansionof the mesangial stalks and capillary walls as a result of extracellularaccumulation of haphazardly arranged fibrils measuring approximately16 nm in thickness. Podocyte foot processes were diffusely effaced.There was no evidence of fibrillary deposits in the tubularbasement membranes or interstitium. The diagnosis of fibrillaryglomerulonephritis was established on the basis of the ultrastructuralfindings in conjunction with the negative Congo Red stain andtypical histologic and immunohistochemical features.
Fibrillary glomerulonephritis is a morphologically defined entitycharacterized by glomerular accumulations of nonbranching, randomlyarranged fibrils that are ultrastructurally indistinguishablefrom amyloid fibrils but differ from amyloid by virtue of theirlarger size and lack of reactivity with Congo Red and otherreagents that are histochemically reactive with amyloid.1–4As in our case, this diagnosis requires electron microscopicidentification of characteristic infiltrating fibrils withinglomerular structures. It has been identified in approximately0.5 to 1.0% of native kidney biopsies in at least three largebiopsy series reported to date.3–5 It is distinct fromother, much rarer processes involving deposition of glomerularfibrils such as occur with fibronectin glomerulopathy and collagenofibroticglomerulopathy.6
Clinically, fibrillary glomerulonephritis most often presentsin middle-aged to older patients (mean age 55 to 60 yr), althoughthe age range is wide and this disease has rarely been reportedin the pediatric population. Patients typically present withproteinuria, 50% within nephrotic range. Hematuria and hypertensionare also common presenting conditions (60 and 77%, respectively,in some series).5 No clinical laboratory findings are specificfor this condition; all of the usual serologies obtained forthe workup of various forms of glomerulonephritis are typicallynegative and/or normal; however, there was a report of severalpatients who had features of fibrillary glomerulonephritis andconcomitant infection with hepatitis C virus.7
The outcome for patients with this disease is frequently poor.Progression to end-stage renal disease occurs in approximatelyhalf of the patients within several years of diagnosis.4,5 Thereare no known established therapeutic regimens for this disease,and no organized clinical trials have tested the efficacy ofany proposed clinical approach.8 Several studies have documentedthe recurrence of this disease in renal transplants, which insome cases has resulted in nephrotic syndrome and/or allograftloss.1,8–10
The histologic appearance of fibrillary glomerulonephritis issomewhat heterogeneous. Common histologic patterns include thoseof a membranoproliferative glomerulopathy, diffuse proliferativeglomerulonephritis, mesangial proliferative glomerulopathy anda smaller number of cases in which the pattern and distributionof the fibrillary deposits is similar to that of membranousnephropathy.5 In many cases, a pattern of infiltration of glomerularstructures by amorphous acellular material is the most strikingfeature unaccompanied by prominent cellular proliferation (Figure 1).This material can be seen to infiltrate mesangial regions andperipheral capillary walls, although in rare cases there maybe no detectable histologic alterations and the glomerular appearancemay be indistinguishable from minimal-change disease. Some studieshave suggested that as many as 20% of cases may be accompaniedby crescent formation,4,5 although this number is high in ourexperience and the crescents are rarely a dominant feature.Most often, the glomeruli are without prominent inflammatorycell infiltration. Essential to the diagnosis, as already indicated,is the absence of reactivity with Congo Red or other agentstypically used for the histochemical demonstration of amyloidin tissues. Immunofluorescence findings most often reveal polyclonaldeposits of immunoglobulin (Ig), typically IgG, and light chains,but a small percentage of these patients have monoclonal oroligoclonal Ig deposition characterized by deposits of Ig heavy-chainand one light-chain subclass (e.g., light chain) but not theother.1–3 When studied by IgG subclass typing sera, depositionof IgG4 and IgG1 predominates in fibrillary glomerulonephritis,a finding of uncertain pathophysiologic significance.4,5 Thecharacteristic ultrastructural finding is an amyloid-like processin which glomerular structures are infiltrated by randomly arranged,nonbranching fibrils that typically measure 12 to 24 nm in diameter,with measurements most frequently being approximately 18 to20 nm (Figure 2).1–4 This contrasts with the usual fibrilsize in amyloid (typically reported as being between 8 and 15nm, but with the most typical measurements being 8 to 12 nm).2Fibrils in fibrillary glomerulonephritis are often enmeshedin regions in which there is electron lucency. Granular electron-densedeposits, similar to conventional immune deposits, may alsobe present and admixed among the accumulations of fibrils.
Figure 2. Ultrastructural features of the fibrils of amyloid (A), fibrillary glomerulonephritis (B), and microtubules of immunotactoid glomerulopathy (C). The amyloid fibrils are randomly arranged and nonbranching. In fibrillary glomerulonephritis, the fibrils are morphologically indistinguishable from those of amyloid but thicker. Immunotactoid glomerulopathy is characterized by microtubules that are hollow when viewed on end.
Fibrillary glomerulonephritis, as the name suggests, is primarilya disorder involving glomeruli. Uncommonly, the fibrillary depositsmay also involve tubular basement membranes. There are scatteredcase reports of concomitant deposition of fibrillary depositsin extrarenal sites such as heart and lung, but inspection ofpublished illustrations suggests to us that these reports beinterpreted with caution.
FIBRILLARY GLOMERULONEPHRITIS VERSUS IMMUNOTACTOID GLOMERULOPATHY
An entity that is often considered within the spectrum of renaldiseases as fibrillary glomerulonephritis is immunotactoid glomerulopathy.In the view of some, immunotactoid glomerulopathy is a unifyingterm for cases of glomerular deposition of both the amyloid-likefibrils described as fibrillary glomerulonephritis and casesin which the glomerular deposits consist of larger microtubularstructures that also fail to react with histochemical stainsfor amyloid in tissue sections.11,12 These microtubular structuresoften measure >30 nm in diameter with most reported caseshaving measurements ranging from 34 to 49 nm.2,3 We and othershave taken the approach that immunotactoid glomerulopathy isa term best used in a more restricted sense, to define a morphologicentity characterized by glomerular deposits of Ig organizedas large microtubules.2,3,5,13,14 The diagnosis requires ultrastructuraldemonstration of these microtubules, which are generally butnot invariably >30 nm in diameter. When so defined, immunotactoidglomerulopathy is a rare entity, occurring one tenth as frequentlyas fibrillary glomerulonephritis.4 Like fibrillary glomerulonephritis,this entity occurs in an older population, with most reportedpatients >50 yr of age. Patients typically present with nephroticsyndrome (50% in one series5) but may also have features ofhematuria and renal insufficiency (five out of six patientsin one of the largest series reported to date5). Specific therapeuticapproaches have not been established. Recurrent disease hasbeen reported in renal allografts.
There are clinical features that also support the notion thatthe morphologic entity of immunotactoid glomerulopathy is bestconsidered as a distinct clinical entity. These patients havea greater predisposition to an underlying lympho-plasmacyticdisorder.2,3,5,13,14 This is supported by immunofluorescencestudies on renal biopsies in which clonality (i.e., restrictionto one light-chain subclass) of the deposits frequently canbe demonstrated by immunofluorescence microscopy. The characteristicorganized nature of the microtubular deposits is a feature thatis also occasionally encountered in patients with cryoglobulinemiaand/or systemic lupus erythematosus, and the morphologic findingsof microtubular deposits in a renal biopsy should prompt considerationof these clinical possibilities.
Although there has been a spirited discussion among membersof the renal community over the issue of whether fibrillaryglomerulonephritis and immunotactoid glomerulopathy are bestconsidered as one entity or two, this issue of classificationseems less important than the recognition that both of theseentities can and should be morphologically distinguished fromamyloidosis and that the recognition of these morphologic patternscan suggest important clinical disease considerations that shouldbe evaluated in affected patients, such as cryoglobulinemia,systemic lupus, and perhaps hepatitis C virus infection.5,11,13Table 1provides key features for distinguishing amyloidosis, fibrillaryglomerulonephritis, and immunotactoid glomerulopathy.
Table 1. Clinicopathologic features that distinguish fibrillary glomerulonephritis from morphologically similar immunopathologic features of fibrillary/microtubular glomerulopathies
Despite the clear definitions for classic manifestations ofthese entities provided in Table 1, there are cases in whichthe differential diagnosis of fibrillary glomerulonephritisand immunotactoid glomerulopathy poses difficult challengesfor the pathologist. These entities can be overlooked when electronmicroscopy is not performed on a renal biopsy; there is no othermeans of establishing this diagnosis. This is a particular problemwhen the infiltrating fibrils of fibrillary glomerulonephritisare confined to subepithelial portions of the glomerular capillarywalls, giving an appearance of membranous glomerulopathy byimmunofluorescence microscopy and thus obviating the need forultrastructural examination in the minds of some. A second sourceof error is not to measure the fibrils or, just as important,not to measure them accurately with a properly calibrated electronmicroscope. A more difficult challenge is finding fibrils ormicrotubules of a measured size at the far ends of the acceptedspectrums. In those uncommon cases of fibrillary glomerulonephritiswith smaller fibrils, there is overlap with amyloid, and inthese circumstances, in which diagnostic certainty may not beachievable, it is our practice to rely heavily on the resultsof Congo Red staining (or staining with other dyes that identifyamyloid, such as Thioflavine T) to make a diagnostic distinction.Sometimes the fibrils may have an atypical ultrastructural appearance:they may be curved rather than straight, and some fibrils mayappear "hollow" when viewed on end. In these unusual cases,it must be acknowledged that the best judgment of the pathologistwill be as important as published criteria in reaching or excludingthis diagnosis.
One additional consideration is the substructural organizationof Ig deposits in certain systemic disorders. Deposits of cryoglobulinscan be microtubular and indistinguishable from those of immunotactoidglomerulopathy; for this reason, cryoglobulinemia should bea diagnostic consideration whenever such deposits are encountered.Ig deposits in lupus nephritis can demonstrate substantial organizationwith a "fingerprint" appearance that is not easily confusedwith fibrillary glomerulonephritis; however, the immune depositsin lupus nephritis can occasionally have a randomly arrangedfibrillar substructure indistinguishable from fibrillary glomerulonephritis,particularly lupus membranous glomerulonephritis, and it isonly by clinicopathologic correlation that the correct diagnosisof lupus nephritis may be achieved in these cases.
The pathogenesis of fibrillary glomerulonephritis is unknown.Investigations into pathogenesis have been hampered by the absenceof an animal model. One clue to the pathogenesis of this diseasehas been the immunoelectron microscopic localizations of IgG;the complement component C3 and amyloid P component to individualfibrils; but not labels for matrix and microfibrillar proteinsincluding collagen type IV, heparan sulfate proteoglycan, fibronectin,and fibrillin.15 These studies provide the best evidence todate that the fibrils in this disorder are composed of Ig, althoughthey do not conclusively prove this proposition because it remainspossible that the Ig identified is secondarily bound to a fibrillarprotein not recognized by the antisera used. To our knowledge,the fibrils of fibrillary glomerulonephritis have not been extractedfrom biopsy, nephrectomy, or autopsy tissues; therefore, biochemicalapproaches to characterize the involved proteins have yet tobe attempted.
Alpers CE, Rennke HG, Hopper JJR, Biava CG: Fibrillary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 31: 781–789, 1987[Medline]
Alpers CE: Immunotactoid (microtubular) glomerulopathy: An entity distinct from fibrillary glomerulonephritis? Am J Kidney Dis 19: 185–191, 1992[Medline]
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Abstract
CASE PRESENTATION
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light chain (each trace). There was no significant staining of the glomeruli for IgA, IgM, C3, C1q, fibrinogen, or albumin. Ultrastructural examination of two glomeruli revealed expansion of the mesangial stalks and capillary walls as a result of extracellular accumulation of haphazardly arranged fibrils measuring approximately 16 nm in thickness. Podocyte foot processes were diffusely effaced. There was no evidence of fibrillary deposits in the tubular basement membranes or interstitium. The diagnosis of fibrillary glomerulonephritis was established on the basis of the ultrastructural findings in conjunction with the negative Congo Red stain and typical histologic and immunohistochemical features. 
