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