fibrillary glomerulonephritis and immunotactoid...

Kidney International, Vol. 62 (2002), pp. 1764–1775

Fibrillary glomerulonephritis and immunotactoid(microtubular) glomerulopathy are associated withdistinct immunologic features

FRANK BRIDOUX, VALERIE HUGUE, OLIVIER COLDEFY, JEAN-MICHEL GOUJON,MARC BAUWENS, ANNE SECHET, JEAN-LOUIS PREUD’HOMME, and GUY TOUCHARD

Department of Nephrology, Department of Pathology, and Laboratory of Immunology and Immunopathology(CNRS ESA 6031), University Hospital, Poitiers, France

Conclusions. The identification of ultrastructural patterns inFibrillary glomerulonephritis and immunotactoid (microtubu-these nephropathies is important. GN with organized microtu-lar) glomerulopathy are associated with distinct immunologicbular monoclonal deposits (GOMMID) probably accounts forfeatures.a large proportion of immunotactoid (microtubular) GN cases.Background. The clinical relevance of distinguishing two

types of glomerulonephritis (GN) with non-amyloid organizedimmunoglobulin (Ig) deposits—fibrillary GN (FGN) and im-munotactoid (microtubular) GN (IT/MTGN)—on the basis of Non-amyloid glomerulopathies with Congo red-nega-ultrastructural organization, is debated.

tive organized immunoglobulin (Ig) deposits display twoMethods. Twenty-three patients with organized glomerularcharacteristic patterns on electron microscopy (EM):Ig deposits were classified into two groups based on the fibrillar

or microtubular ultrastructural appearance of the deposits. randomly arranged (pseudo-amyloid) fibrils, or microtu-Kidney biopsy samples were studied by immunofluorescence bules, which are usually larger and ordered in parallelmicroscopy, using anti-light chain conjugates (all cases) and arrays [1–23]. It is currently unclear whether this mor-anti-IgG subclass conjugates (13 patients). In each group, we

phological distinction is relevant. Certain investigatorsstudied clinicopathological features, associated monoclonalconsider this distinction to have no clinical or pathophys-gammapathy (detected by immunoelectrophoresis and/or im-

munoblot) or B-cell lymphoproliferative disease, effects of che- iological basis; they suggest that fibrillar and microtubu-motherapy and long-term renal outcome. lar Ig deposits should be considered simply as variants

Results. In 14 IT/MTGN and 9 FGN patients, clinical symp- of the same glomerulopathy, referred to as fibrillary-toms [hypertension, nephrotic syndrome (NS) and hematuria]immunotactoid glomerulonephritis (GN) [3, 15, 18, 20].and the mean diameters of the substructures were similar. InThey also advocate limiting this diagnosis to patients with13 IT/MTGN patients, glomerular (IgG1, 2 or 3) deposits were

monotypic (�, 7 cases; �, 6 cases). Glomerular deposits were as- primary renal disorders, excluding patients with mono-sociated with a monoclonal Ig of the same isotype in eight pa- clonal gammapathy, systemic diseases or lymphoproli-tients, detected in the serum (5 cases), and/or in the cytoplasm ferative disorders [3, 7]. Others claim that it is essential toof lymphocytes (4 cases), and with lymphoproliferative disease

distinguish between immunotactoid (microtubular) GNin seven patients. The ultrastructural features of monoclonaland fibrillary GN (FGN) [10, 12–14, 19]. In immunotac-Ig inclusions in lymphocytes were similar to those of glomerular

microtubular deposits. In contrast, none of the FGN patients toid GN, defined by the presence of orderly arrangedpresented lymphoplasmocytic proliferation or paraproteinemia. microtubules that are usually more than 30 nm in diame-Glomerular Ig deposits were polyclonal in eight cases and con- ter, glomerular Ig deposits are often monotypic. Immu-tained IgG4 in all three cases studied. Although patient and re-

notactoid GN may be associated with monoclonal gam-nal survival did not differ significantly between the two groups,mapathy and/or hematological malignancy with improvedchemotherapy led to remission of NS in ten IT/MTGN patients,

with parallel improvement in hematological parameters. renal prognosis upon chemotherapy [6, 10, 13, 14]. Inter-estingly, monoclonal microtubular Ig deposits with a mi-crotubule diameter smaller than that commonly ob-Key words: glomerulonephritis. monoclonal gammapathy, ultrastruc-served in immunotactoid GN have been described in ature of GN, nephropathy, non-amyloid glomerulopathies, morphology

of Ig deposits. few patients with chronic lymphocytic leukemia or re-lated B-cell lymphoma [6, 14, 24]. In contrast, in FGNReceived for publication December 17, 2001patients, the fibrils are consistently less than 30 nm inand in revised form June 11, 2002

Accepted for publication June 13, 2002 diameter and there is usually no underlying hematologicaldisease [5, 8, 12, 13, 22, 23]. A predominance of poly- 2002 by the International Society of Nephrology

1764

Bridoux et al: Glomerular organized immunoglobulin deposits 1765

clonal IgG4 in glomerular deposits also has been re- by EM on a scale from 0 to 4�, and the external diameterwas measured by two methods. Specimens were photo-ported in patients with FGN [12, 16, 23], but not in those

with microtubular deposits [3, 6, 14]. This controversy graphed at an original magnification of �50,000 and wereexamined on prints at a magnification of approximatelyremains unresolved due to conflicting reports, with anti-

light chain antibody-based studies of biopsy specimens �120,000. Fibrils and microtubules were measured usingan integrated scale: substructures with well-defined out-often incomplete and the frequent exclusion of patients

with dysproteinemias. Sensitive methods, such as immu- lines on transverse sections were reported on the inte-grated scale and the mean external diameter was ob-noblotting, to screen for small amounts of monoclonal

components, or to detect associated lymphoproliferative tained by dividing the length of the scale (in nm) by thenumber of substructures included in the scale. In 16disorders, rarely have been employed [6, 14], even by

those considering paraproteinemia to be an exclusion cases, values were compared with those obtained directlyfor ultra-thin sections at a high magnification (�20,000)criterion. Our current retrospective study recruited 23

patients with non-amyloid organized glomerular Ig de- using software (MEAS) run directly on the electron mi-croscope (JEM-1010; JEOL, Tokyo, Japan); the meanposits, and classified them into two groups based on the

fibrillar or microtubular appearance of the deposits. All diameters were 15.0 � 6.6 nm and 13.8 � 6.9 nm, respec-tively. We also measured plasma membranes, collagenkidney biopsy samples were studied by immunofluores-

cence (IF) microscopy, using anti-light chain conjugates. fibers and amyloid fibrils as controls (Fig. 4 a to c).Results are expressed as the mean � SD of ten randomIn each group, we studied correlations between the ultra-

structural pattern of glomerular deposits and clinical and measurements. Parallel arrays of microtubules were de-fined as at least four microtubules arranged in parallel,pathological features, associated monoclonal gammapa-

thy or B-cell lymphoproliferative disease, the effects of in close proximity. In 13 patients, peripheral blood lym-phocytes (PBL) were processed for EM; in patient 5,chemotherapy, and long-term renal outcome.the kidney biopsy sample (Fig. 4g) and PBL were sub-jected to immunoEM, as previously described [6].

METHODS

Patients Immunologic and virologic studies

Levels of complement, antinuclear and anti-DNA an-Twenty-three patients referred to 15 nephrology de-partments between 1980 and 1997 were included in this tibodies were determined by standard methods. Hepati-

tis B virus (HBV) and hepatitis C virus (HCV) infectionsstudy. Inclusion criteria based on light, electron (EM)and IF microscopy studies of renal biopsy samples were were detected by enzyme-linked immunosorbent assay

(ELISA) and/or polymerase chain reaction (PCR).(1) extracellular glomerular Ig deposits; (2) negative forCongo-red staining; and (3) organization at the ultra- Serum samples from all patients were collected and

processed at 37�C and were repeatedly tested for cryoglo-structural level, where pseudo-amyloid fibrillary depositswere classified as FGN, and microtubular deposits with bulins. Serum and urine monoclonal Ig were detected

by conventional electrophoretic and immunoelectropho-a distinct hollow core, arranged at least focally in parallelarrays, were classified as immunotactoid (microtubular) retic (IEL) analysis. Immunoblotting was used to detect

monoclonal Ig in 18 patients and to determine mono-GN (IT/MTGN).Patients with connective tissue diseases, light chain clonal Ig subclasses, using subclass-specific mAbs, in five

patients [28]. We also studied the surface and cytoplas-deposition disease (LCDD) or cryoglobulinemic glomer-ulonephritis were excluded. Chronic B-lymphocytic leu- mic Ig (SIg, 10 patients; cIg, 12 patients) of PBL and/or

bone marrow lymphocytes by direct IF as previouslykemia (CLL), small lymphocytic non-Hodgkin’s lym-phoma and monoclonal gammapathy of undetermined described [6]; anti-IgG subclass antibodies were used in

patients 2, 5, 7, 10 and 14.significance (MGUS) were diagnosed according to theusual criteria [25–27].

Statistical analysisPathological studies The two groups of patients were compared using Fish-

er’s exact test for qualitative data. Quantitative data wereAll kidney biopsy samples were processed for light,electron and IF microscopy, according to standard tech- expressed as mean � SD and were compared using the

Student t test or the Mann-Whitney test as appropriate.niques. They were examined simultaneously by two pa-thologists, independently and without knowledge of theclinical data. In 13 patients, subclasses of glomerular

RESULTSIgG were determined using mouse monoclonal anti-�1,

Renal symptomsanti-�2, anti-�3 and anti-�4 antibodies (mAbs) (NL 16,ZG 4, RJ 4; Unipath, Bedford, UK; and HP 6014; Bind- Fourteen Caucasian patients (4 women, 10 men) ful-

filled the criteria for IT/MTGN and nine (4 women, 5ing Site Ltd., Birmingham, UK). Deposits were graded

Bridoux et al: Glomerular organized immunoglobulin deposits1766

Table 1. Renal symptoms at presentation

Age Proteinuria Microscopic Initial SCr

Case no. Sex years Hypertension g/day NS hematuria mg/dL

IT/MTGN1 M 75 � 36 � � 1.92 M 70 � 6.0 � � 1.13 M 66 � 10 � � 1.54 M 53 � 10 � � 1.15 F 57 � 23 � � 1.06 F 73 �a 3.8 � � 0.77 M 44 � 8.0 � � 0.98 M 48 � 9.5 � � 1.49 M 47 � 20 � � 1.5

10 M 72 � 15 � �b 2.811 M 73 � 1.4 � �b 3.812 F 30 � 7.0 � � 0.813 F 74 � 2.7 � �b 1.914 M 45 � 3.4 � � 1.1mean�SD 59�15 11.1�9.6 1.5�0.9

FGN15 M 62 � 11.5 � � 2.916 F 68 � 3.2 � � 1.217 F 68 �a 4.5 � ND 1.618 M 25 � 1.8 � � 1.119 M 71 � 5.2 � � 2.120 M 45 � 2.5 � � 0.921 F 58 � 6.5 � � 1.022 M 61 � 1.8 � � 1.423 F 54 � 3.5 � � 2.4mean�SD 57�14 4.5�3.1 1.6�0.7

P value 0.66 0.73 0.40 0.06 0.07 0.62 0.80

Abbreviations are: NS, nephrotic syndrome; SCr, serum creatinine concentration; ND, not done; IT/MTGN, immunotactoid (microtubular) glomerulonephritis;FGN, fibrillary glomerulonephritis. Cases 1, 4, 5 and 2, 3, 7, 13 have been published elsewhere [6, 14]

a 200/100 mm Hgb With one or more episodes of macroscopic hematuria

men) fulfilled those for FGN. At diagnosis, there was liferative GN (Fig. 2 a, b). Global sclerosis of up to 50%of the glomeruli was seen in nine of 13 patients with IT/no significant difference between IT/MTGN and FGN

patients in age, serum creatinine level (SCr), incidence of MTGN and seven of nine patients with FGN. IT/MTGNpatients 9 and 13 had mild extra-capillary proliferation.microscopic hematuria, hypertension, and renal failure

(SCr 1.2 mg/dL). Although proteinuria and the inci- In seven patients with IT/MTGN (cases 1–4, 8, 10, 13),and three with FGN (cases 17, 18, 21), a few polymorpho-dence of nephrotic syndrome (NS) were higher in the

IT/MTGN group, the difference was not significant (Ta- nuclear leukocytes were observed within capillary loops.Eight patients with IT/MTGN and five with FGN hadble 1). Three patients in the IT/MTGN group had macro-

scopic hematuria. Hypertension was moderate in all but mild-to-moderate interstitial fibrosis. Interstitial tumorallymphocytic infiltration was observed in four IT/MTGNone case in each group.patients with B-cell lymphoproliferative disease.

Renal pathology and immunohistochemistry Diffuse, in some cases irregular, granular glomerularcapillary wall staining with anti-� and anti-C3 conjugatesLight microscopy patterns did not differ significantly

between the two groups (Tables 2 and 3). Atypical mem- was observed in all IT/MTGN patients, with segmentaland focal staining of the mesangium in most cases (Fig. 1b).branous GN lesions, associated with segmental mesan-

gial matrix expansion and hypercellularity, were observed Seven patients had C1q deposits. In patient 8, glomerularhyaline thrombi were stained with anti- conjugate, andin ten IT/MTGN and four FGN patients (Fig. 1a). In IT/

MTGN patients 8 and 9, deposits formed eosinophilic a similar staining pattern was observed for glomerularbasement membranes (GBM) with anti- and anti-�hyaline pseudo-thrombi. In patient 8, whose serum con-

tained a monoclonal IgM�, a few hyaline (amorphous) conjugates. In FGN patients, deposits were mostly mes-angial, associated with diffuse, predominantly sub-epi-glomerular thrombi were present together with pseudo-

thrombi (showing microtubular organization on EM). thelial binding to the GBM. The deposits were stainedwith anti-� and anti-C3 conjugates, and also with anti-Four patients with IT/MTGN and one with FGN had

membranoproliferative GN with a lobular pattern in conjugate in two patients and with anti-� conjugate intwo further cases. C1q deposits were present in the fourthree cases. Four patients with FGN had mesangial pro-


FGN cases studied. The subclasses of IgG deposits weredetermined in ten IT/MTGN patients: �1 in five cases,�2 in three and �3 in two, with no staining with otheranti-IgG subclass reagents (Fig. 1b). In FGN patients,IgG subclasses were determined in three cases: depositsstained for �4 in patients 18, 19 (Fig. 2c) and for both�4 and �1 in patient 15. In all IT/MTGN patients exceptpatient 1, glomerular light chain deposits were mono-typic (� in 7 and � in 6 cases). In contrast, depositswere stained with both anti-� and anti-� conjugates inall patients with FGN, except for patient 21, in whomonly � determinants were detected. The difference inincidence of monotypic deposits between the two groupswas highly significant (P � 0.001).

On EM, all the cases of IT/MTGN showed extracellu-lar microtubules arranged in densely packed arrays, withwell defined borders. In case 12, microtubular organiza-tion was focal. Microtubules had a central lumen in allcases (Figs. 1 c, d and 5). The external diameter rangedfrom 9 to 45 nm (mean 15.2 � 7.3 nm; Figs. 4 e and hand 5). Microtubules were located predominantly in thesubepithelial space and mesangium. They were also foundon tubular basement membranes in case 2. Microtubulesfrom patient 9 displayed a 37.9 � 5.6 nm external diame-ter and 70 A cross-striation (Fig. 4h). In patient 5 (withglomerular IgG1� deposits), microtubules reacted withanti-� and anti-� peroxidase conjugates using immu-noEM (Fig. 4g). In FGN patients, deposits with poorlydefined borders, were organized into unbranched, ran-domly oriented extracellular fibrils of 7 to 26 nm in diam-eter (mean 15.8 � 3.5), with no central lumen (Fig. 4d).Fibrils were predominantly mesangial and subepithelial.In some cases, fibrils extended through the lamina densaof the GBM (Fig. 2d). Organized deposits were not de-tected within intravascular spaces.

Immunologic, virologic and hematologic findings

Antinuclear antibodies were present at low titers ( 1/100) in three of 12 patients with IT/MTGN and three ofnine patients with FGN. None of the patients had anti-DNA antibodies. Rheumatoid factor was detected at alow titer (1:20) in patient 13. CH50 levels were moder-ately low in IT/MTGN cases 1, 2, 4 to 6 and in FGNpatient 18. C3 and C4 levels were low in patient 1 andpatient 4 had low C1q and C2 levels but normal C3and C4 levels. There was no significant difference inthe incidence of complement abnormalities between IT/MTGN and FGN patients (P � 0.34). Type I cryoglo-bulin (IgG �) was detected transiently (1 of three samplesstudied), in small amounts, only in patient 4.

Of the five IT/MTGN and five FGN patients testedfor HBV, only patient 1 had HBs antigen and anti-Hbeantibodies. Patient 15 had anti-HBs and anti-HBc anti-

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Table 3. Renal biopsy findings in patients with FGN

Patient no.

15 16 17 18 19 20 21 22 23

Light microscopyPattern of glomerulopathy Atypical Atypical MPGN Mes GN Mes GN Mes GN Atypical Mes GN Atypical

MGN MGN MGN MGNCrescents % 0 0 0 0 0 0 0 0 0Obsolescent glomeruli % 22 11 12 20 43 0 20 0 50Glomerular thrombi � � � � � � � � �Interstitial fibrosis Moderate � Moderate � Mild � � Mild Moderate

ImmunofluorescenceHeavy chain �4 � �1 � � �4 � � �4 � � � � � � � �Light chain � � � � � � � � � � � � � � � � � � � � � � � � �C3 � � � � � � � � �C1q ND ND ND � ND � ND � �

Electron microscopyLocation of microfribrils Epi 2� Epi 4� Epi 3� Epi 2� Epi 1� Epi 3� Epi 4� Epi 1� Epi 2�

Endo 1� Endo 1� Endo 2� Endo 1� Endo 2� Endo 1� Endo 1� Endo 2� Endo 2�Mes 3� Mes 4� Mes 2� Mes 4� Mes 4� Mes 3� Mes 3� Mes 3� Mes 3�CW 1� CW 2� CW 2� CW 1� CW 0 CW 1� CW 2� CW 1� CW 0

Microfibril diametera nm 13.3�1.1 16.4�1.6 12.0�1.9 15.1�2.2 15.6�1.0 15.1�1.9 12.1�1.2 19.4�4.8 22.9�1.9

Abbreviations are: MPGN, membranoproliferative glomerulopathy; MGN, membranous glomerulopathy; Mes GN, mesangial glomerulopathy; Mes, mesangial;Epi, subepithelial; Endo, subendothelial; CW, glomerular capillary wall.

a Results are expressed as mean � SD of ten random measurements (manual method)

Fig. 1. Immunotactoid (microtubular) glomer-ulonephritis (patient 2). (a) Light micros-copy. Atypical membranous glomerulonephri-tis (GN), with mesangial matrix expansion,increased mesangial cellularity and diffuse glo-merular capillary wall thickening by an eosin-ophilic material. Capillary lumens are some-times occluded by both mesangial and parietallesions (trichrome light green staining �400).(b) Immunofluorescence microscopy. Mesan-gial and glomerular basement membrane de-posits stained with anti-�2 rhodamine conju-gate (�500). A similar staining pattern wasobserved with anti-�, anti-� and anti-C3 con-jugates. Deposits did not stain with anti-�,anti-�1, anti-�3, anti-�4, anti-� and anti- con-jugates. (c and d) Electron micrographs (finalmagnification �33,000 and �110,000, respec-tively) showing highly organized, osmiophilicmesangial deposits made up of parallel micro-tubules of 16.7 � 1.2 nm diameter with a clearhollow center.

antibodies nor HCV RNA were detected in any of the and CD19. In patients 1, 3, 5, and 10, hematologicaldisease had been diagnosed six, two, six and three yearspatients studied (IT/MTGN, 5 cases; FGN, 3 cases).

In IT/MTGN patients 1 through 6, the CLL diagnosis before renal presentation, respectively.In five IT/MTGN patients, a serum monoclonal Ig waswas based on the association of bone marrow infiltration

by mature lymphocytes (30%), high blood lymphocyte detectable by IEL analysis. Western blots, performedin 11 cases, gave a strong signal for the monoclonal Igcounts (5 � 109/L), and lymphadenopathies in five

cases (Table 4). Patient 7 was diagnosed with small detected by IEL analysis and for IgG� in patient 12.These monoclonal Ig were identical to those found inlymphocytic non-Hodgkin’s lymphoma, but this diagno-

sis could not be unequivocally confirmed due to the ab- the glomerular deposits of patients 4, 9, 10 and 12. Inthe remaining patients, immunoblot results were nega-sence of immunophenotypic and cytogenetic studies. In

cases 2, 3 and 7, blood lymphocytes co-expressed CD5 tive (case 14), or showed non-significant amounts of mul-


Fig. 2. Fibrillary glomerulonephritis. (a) Lightmicroscopy (patient 20). Glomerulus showingmesangial expansion by PAS-positive mate-rial and some thickened capillary walls, withno increase in glomerular cellularity (PASstaining �400). (b) Light microscopy (patient18). Mesangial deposits were not stained bysilver impregnation. Focal duplication of glo-merular basement membranes was observed(Marinozzi’s silver staining �312). (c) Immu-nofluorescence microscopy (patient 19). Dif-fuse granular staining of the mesangium andthe capillary walls with anti-� conjugate (�500).A similar staining pattern was observed withanti-�4, anti-�, anti-�, and anti-C3 reagents.(d) Electron microscopy (patient 16). Intra-and epi-membranous randomly oriented fi-brils of 16.4 � 1.6 nm in diameter, without ahollow core. Fibrils formed spicules notchingthe podocyte plasma membrane (final magni-fication �20,000). Congo red-staining was nega-tive (not shown).

Fig. 3. (a) IT/MTGN (patient 2). Immuno-fluorescence microscopy of peripheral bloodlymphocytes stained with anti-�2 conjugate(�1250). Strong cytoplasmic staining of leuke-mic lymphocytes with an unusual perinuclearpattern often predominant at a cell pole. Asimilar pattern was observed with anti-� con-jugate, but staining with anti-�, anti-�1, anti-�3, anti-�4, anti- and anti-� conjugates wasundetectable. (b) Same patient and same pat-tern of cytoplasmic fluorescence of interstitialleukemic lymphocytes in renal biopsy (anti-�conjugate �500). A similar staining patternwas observed with anti-� conjugate but not withanti-�, anti- and anti-� conjugates. (c and d)IT/MTGN (patient 7). Electron microscopy ofbone marrow (c) (final magnification �16,000)and peripheral blood lymphocytes (d) (finalmagnification �50,000) showing numerous cis-ternae of rough endoplasmic reticulum contain-ing straight microtubules 10.4 � 1.1 nm in exter-nal diameter (final magnification �135,000)

tiple monoclonal Ig (cases 3, 6, 11), or small amounts of MTGN patients 13 and 14 (Table 4). Monotypic B lym-phocyte populations were identified based on SIg expres-a single monoclonal Ig (cases 2, 7, 13) of the same isotype

as the glomerular deposits (patient 2; Table 4). In three sion in the five CLL patients studied (patients 1 to 5).We analyzed cIg in lymphocytes and detected intracy-patients, small amounts of a �-type Bence-Jones protein

were found. In none of the FGN patients was serum toplasmic crystal-like Ig inclusions in three CLL patients(cases 2, 3 and 5) and in the lymphoma patient (case 7,monoclonal Ig or urinary Bence-Jones protein detect-

able by IEL analysis. Non-significant amounts of multi- in whom no SIg was detectable) (Fig. 3a). The isotypesof the Ig inclusions matched those of the glomerularple monoclonal Ig were found in six of seven patients

whose serum was studied by immunoblotting; no mono- Ig deposits (a minor population of lymphocytes withinclusions of a different IgG subclass also was detectedclonal Ig was detected in the seventh case.

Surface Ig and cIg isotypes were normally distributed in patient 7). Lymphocyte inclusions displayed a microtu-bular organization identical to that of glomerular IgGin the blood and/or bone marrow lymphocytes of IT/


Fig. 4. Electron microscopy. (Bar � 100 nm). (a) Plasma membrane 7.6 � 0.5 nm thick (range 6.5-8.2 nm) (final magnification �110,000). (b)Transverse section and (b�) longitudinal section of collagen microtubules 11.3 � 1.0 nm in external diameter (range 9.5 to 12.5 nm) with distincthollow core, in a patient with diabetic glomerulosclerosis (final magnification �110,000). (c) AL amyloid fibrils 7.0 � 0.4 nm in external diameter(range 6.5 to 7.5 nm; final magnification �110,000). (d) FGN (range 12.8 to 18.6 nm; final magnification �110,000). (e) IT/MTGN (patient 5, samecase as in Fig.4). IgG1� deposits organized in microtubules with a hollow core, 11.3 � 1.3 nm in external diameter (range 8.8 to 12.9 nm) in glomeruli(final magnification �110,000) and ( f ) within cisternae of rough endoplasmic reticulum in blood lymphocytes (mean diameter 10.7 � 1.7 nm, range8.2 to 12.9 nm; final magnification �110,000). (g) IT/MTGN (patient 5). The same glomerular subepithelial microtubules stained with anti-�peroxidase conjugate (final magnification �16,000). Deposits did not stain with anti-� conjugate. (h) IT/MTGN (patient 9). Highly organizedglomerular microtubules 37.9 � 5.6 nm in external diameter (range 30.2 to 44.8 nm) showing a small hollow core 4 to 5 nm in diameter and athick wall on transverse sections. Cross-striation with a periodicity of 70 A is also observed on longitudinal sections (final magnification �110,000).

deposits (Figs. 3 c, d and 4f). In patient 5, immunoEM tal leukemic infiltration, with no amyloidosis or densedeposits in Disse’s spaces (IF study not performed). Pa-confirmed that the intracytoplasmic lymphocyte microtu-

bules consisted of a monotypic IgG�, as did the glomeru- tient 10 presented with severe mononeuritis multiplexof the lower limbs. Peripheral nerve biopsy showed areaslar microtubules (Fig. 4g). Similar intracytoplasmic inclu-

sions, with the same IF and ultrastructural features, were of demyelination and hyperplasia of Schwann’s cells withperineurial Congo red-negative IgG� deposits. These de-observed in lymphocytes infiltrating the renal intersti-

tium in patients 2 and 7 (Table 2 and Fig. 3b). In patient posits displayed a similar ultrastructural microtubularorganization to the glomerular IgG2� deposits (the IgG10, a small percentage of bone marrow plasma cells

stained for the same IgG2� as detected in glomerular subclass of the nerve deposits was not determined). Noneof the patients had acrosyndrome, polyarthralgia ordeposits (Table 4).

Bone marrow examination yielded normal results in other symptoms of cryoglobulinemia.seven FGN patients. None of the patients had lympho-

Treatment and outcomecyte intracytoplasmic monotypic Ig inclusions, evaluatedby direct IF in three cases and EM in two cases. SIg iso- In patients with IT/MTGN, the first-line treatment

was corticosteroids alone (2 cases) or associated withtypes were normally distributed in blood lymphocytesin the one case studied, as were cIg in bone marrow cyclophosphamide or melphalan (2 cases), with cyclo-

phosphamide and vincristine or doxorubicin (2 cases),plasma cells in another patient. None of the patients withFGN developed malignant hematological disease during with chlorambucil (6 cases), or chlorambucil alone (1 case).

Complete (proteinuria �1 g/day, 5 cases) or partial (pro-follow-up.teinuria �3 g/day, 5 cases) remission was achieved in 10

Other manifestations of the 12 nephrotic patients. In five of seven patientswith B-cell lymphoproliferative disease, blood lympho-Patient 6 had dermal capillaritis of the lower limbs,

with fibrin thrombi and granular deposits of fibrin and cyte counts decreased, accompanied by a sharp decreasein the number of circulating lymphocytes containing mi-C1q (but no IgG) on the blood vessel walls. In patient 4,

who had portal hypertension, liver biopsy revealed dif- crotubular inclusions (but not their total disappearance)and NS remission. In patients 2 and 5, NS remission wasfuse regenerative nodular hyperplasia associated with por-


Fig. 5. IT/MTGN (patient 5). Electron microscopy. Voluminous sube-pithelial deposits organized into small microtubules of 11.3 � 1.3 nmin diameter. Microtubules are arranged in parallel arrays, with well-defined borders [final magnification �44,000 (a) and �88,000 (b)]. Oncross sections, a hollow core is clearly observed within the microtubules[final magnification �176,000 (c)].

observed despite persistent lymphocytosis. After treat-ment withdrawal, NS relapsed in six patients, accompa-nied by hematological relapse in cases 3, 4, 6 and 7.Hematological and renal parameters improved followingthe resumption or intensification (cases 3, 6, 7) of chemo-therapy. In two cases, NS persisted despite treatmentwith corticosteroids (patient 13), or corticosteroids withmelphalan, followed by cyclophosphamide and then bycarmustine with doxorubicin, over a nine-year period(patient 9).

Repeat kidney biopsies were performed in four pa-tients. In patient 9, glomerular lesions were unchangedafter two years of treatment, but interstitial fibrosis in-creased. In three patients, NS remission was accompa-nied by the reduction (patient 2) or disappearance (pa-tients 3 and 7) of glomerular IgG deposits and interstitialtumoral lymphocyte infiltrates. However, interstitial scle-rosis progressed in all cases. A third biopsy, performedafter the second relapse of NS in patients 3 and 7, showedthe recurrence of interstitial lymphocyte infiltration andof glomerular microtubular IgG1� deposits. Finally, in

Tab

le4.

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and

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(sta

geB

)36

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o

80%

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od

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%

�2%

bd�

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ain

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LL

(sta

geC

)48

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ymph

o82

%�

�Ig

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�94

%�

2�93

%b

�2�

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(sta

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patient 7, complete hematological and renal remission


with the disappearance of microtubular deposits was for deposited microtubules and fibrils [10, 13, 19]. Ourresults suggest that the smaller mean size of microtubulesachieved by high-dose chemotherapy followed by stem

cell support. Remarkably, six years after diagnosis of IT/ reported here is related to the high prevalence of mono-clonal Ig deposits, and that these immunopathologic fea-MTGN with IgG � monoclonal gammapathy, patient 9

developed purpura, peri-orbital hematomas and heart tures may characterize an entity different from FGN and“classical” immunotactoid GN. As electron-lucent coresfailure, resulting in death after eight years of hemodialy-

sis. He had received multiple chemotherapy regimens (see may be difficult to detect in microtubules for technicalreasons, and also, according to some authors, may beabove). Post-mortem biopsies revealed diffuse pulmo-

nary, myocardial, hepatic, splenic and cutaneous Congo observed in some glomerular non-amyloid fibrils at veryhigh magnifications (usually above �100,000) [3, 10],red-positive � light chain deposits. Two patients with

FGN showed no improvement of proteinuria and renal the distinction between fibrils and microtubules requiresmeticulous morphologic analysis on high-quality ultra-function under treatment (corticosteroids alone in case

23, or with cyclophosphamide in case 16). After a mean thin sections. In our current study, microtubular depositsdiffered from fibrils by three key features on EM: (1)follow-up period of 54 months for the IT/MTGN group

and 56 months for the FGN group (P � 0.95), patient their arrangement, at least focally, in parallel arrays; (2)the presence of a distinct hollow core seen at originalsurvival (71.4 vs. 88.8%, respectively) was found to be

similar for the two groups (P � 0.62). Although the magnifications of less than �50,000; and (3) the well-defined borders of deposits. Glomerular microtubules 8incidence of chronic renal failure (SCr 1.2 mg/dL in 8

of 14 IT/MTGN, 57.1%, vs. in 8 of 9 with FGN, 88.8%; to 10 nm in diameter have been reported before in pa-tients with monoclonal (type I) cryoglobulinemia andP � 0.18) and terminal renal insufficiency requiring dial-

ysis (2 of 14 with IT/MTGN, 14.3%, vs. 4 of 9 with FGN, GN [30, 31]. As some features of immunotactoid GNoverlap those of cryoglobulinemic nephropathies, it has55.8%; P � 0.06) tended to be lower in the IT/MTGN

group, the difference was not significant. been suggested that the organized deposits in immuno-tactoid GN, and also in FGN, may be due to cryoglobu-lins [2, 10, 17, 32]. We did not observe lesions typical of

DISCUSSIONcryoglobulinic nephropathy, macrophagic infiltrates and

In this study, 23 patients with Congo red-negative glo- organized microtubular osmiophilic material in capillarymerular Ig deposits were divided into two groups ac- lumens, or crystal inclusions within endothelial cells andcording to the ultrastructural organization of these de- macrophages [14]. The location of monoclonal Ig depos-posits: randomly oriented fibrils, or parallel arrays of its in immunotactoid GN also is different from that inmicrotubules with a distinct hollow core. The subclassi- cryoglobulinemic kidney [14], with a higher frequencyfication of immunotactoid (microtubular) GN and FGN of subepithelial and intra-membranous deposits. Noneis based principally on measurement of the diameter of of our patients had cutaneous or articular symptoms,these substructures: microtubules have a mean external which commonly are observed in type I cryoglobulinemiadiameter of more than 30 nm whereas fibrils, as reported [33]. None of the patients showed evidence of hepatitishere, are usually about 20 nm in diameter [2, 7, 8, 11–13, C viral infection, which is sometimes associated with17, 19, 20, 22]. In contrast to the results of other groups, FGN or immunotactoid GN [16, 17].we found that with the exception of one patient who As in previous studies [13, 15], the ultrastructural orga-met the usual criteria for immunotactoid GN, the mean nization of glomerular lesions could not be predicteddiameter of the substructures did not differ with their from clinical findings. Light microscopy patterns, consis-ultrastructural fibrillar or microtubular appearance. It tent with the location of the deposits by EM, also lackedshould be stressed that microtubules with diameters com- specificity [7, 13, 20].prised between 16 nm and 22 nm have been described Our study demonstrates the need for thorough immu-before [3, 7, 13, 21, 24, 29], particularly in patients with nohistochemical investigations in cases of GN with orga-monoclonal Ig deposits [3, 7, 21, 24]; they have in some nized Ig deposits. Indeed, the incidence of polyclonalcases been referred to as fibrillary [24], or fibrillary- glomerular IgG deposits in our patients with FGN wasimmunotactoid GN, despite the typical ultrastructural similar to that previously reported [2, 4, 7, 9, 11, 12, 17,appearance and arrangement of microtubules [21], or as 19, 20]. In contrast, IgG deposits were monotypic in allimmunotactoid GN [3, 13, 29]. Thus, size alone, at least but one patient with IT/MTGN, and were clearly mono-in some cases, is an insufficient criterion for the diagnosis clonal in 10 cases. Our results provide further evidenceof the different types of GN with organized Ig deposits of a high prevalence of monoclonal IgG deposits in im-[19, 21]. It has been suggested that differences in the munotactoid GN, from about 20% [7, 13, 18, 20] to 100%methodologies used to measure substructure diameter, [reviewed in 10, 14]. This variability probably resultsor in the physicochemical characteristics of Ig, may ac- from a lack of information on the clonality of the deposits

in many reports [10]. The identification of glomerularcount for the overlap in the reported diameter ranges


IgG subclasses, although incomplete, was consistent with mic reticulum cisternae and may correspond to earlysteps in Ig secretion by activated lymphocytes [38]. Lym-previous results [12, 16, 23]. IgG4 predominated in three

patients with fibrillar deposits for which IgG subclasses phocyte intracytoplasmic monotypic IgG in four IT/MTGN patients and perineurial monotypic IgG depositswere determined, whereas IgG4 was not found in ten

patients with microtubular deposits, as reported in one in one case were organized into microtubular inclusionswith the same ultrastructural pattern and size as glomer-previous case [3]. The presence of polyclonal IgG4 sug-

gests an autoimmune process in FGN and prolonged ular deposits. Thus, microtubular organization may bean intrinsic property of the monoclonal IgG. Further-antigen stimulation may lead to the formation of nephri-

togenic immune complexes with a fibrillary organiza- more, the concomitant decrease in the number of circu-lating lymphocytes containing monotypic Ig inclusions,tion due to the compactness and rigidity of IgG4 [19].

Deposits were not strictly monoclonal in IT/MTGN pa- with NS remission induced by chemotherapy, is consis-tent with a relationship between the rate of formationtients in whom serum monoclonal IgM� was detected.

In case 8, monoclonal IgG � microtubular deposits were of microtubular glomerular deposits and the number ofleukemic lymphocytes producing the nephrotoxic Ig.present, along with non-organized IgM� glomerular hya-

line thrombi, which are commonly observed in Walden- Such lymphocyte inclusions have not been described incases of FGN. Monoclonal Ig tend to aggregate or tostrom’s macroglobulinemia [34]. The staining pattern for

patient 1 may reflect an anti-IgG activity of the mono- crystallize due to autoreactivity [39, 40] or structuralabnormalities [41, 42]. The primary structure of the vari-clonal IgM, a common property of serum and CLL lym-

phocyte membrane-bound monoclonal IgM [35], or the able region is involved in renal lesions due to monoclonallight chains [36, 41, 43, 44], but also in those secondarysecondary deposition of polyclonal Ig. Such deposition

was recently suggested in two patients with hepatitis C to entire monoclonal Ig. In a murine model of cryocrys-talglobulinemia, induced by injection of a hybridomaand immunotactoid GN with IgG deposits showing no

significant monotypic light chain predominance [17]. clone producing a monoclonal IgG3�, the deletion ofthree amino acids in the first hypervariable region of theThe prevalence of paraproteinemia and lymphopro-

liferative disorders in patients with immunotactoid GN light chain inhibited the formation of highly organizedcrystalline microtubular mesangial and subendothelialis probably underestimated, as the available information

concerning IEL analysis of serum and/or urine is limited deposits, which were replaced by amorphous precipitatesin glomerular capillary lumens, similar to those in human[10]. Moreover, monoclonal gammapathies and B-cell

lymphomas were considered to be exclusion criteria in hyperviscosity syndrome [45]. In patient 9, immunotac-toid (microtubular) GN with IgG� deposits was followedsome previous large series. Sensitive techniques should

be systematically used to determine the relationship be- by systemic AL amyloidosis. The simultaneous occur-rence of glomerular organized fibrillary monoclonal IgM�tween FGN/immunotactoid GN and paraproteinemia.

Our results confirm that (a) immunoblotting may detect deposits and of � amyloid deposits has been reportedbefore [46]. Amyloidosis in our patient may have resultedparaproteinemia not detected by IEL alone; (b) immu-

notactoid (microtubular) GN with monoclonal Ig depos- from the emergence of a variant clone, as chemotherapyis known to induce mutations in Ig genes [47].its may occur with no detectable monoclonal serum or

urine component; and (c) if present, the monoclonal In conclusion, we believe that the distinction betweenFGN and immunotactoid (microtubular) GN is of clini-serum component may be not responsible for the orga-

nized glomerular Ig deposits. These features resemble cal importance. FGN and immunotactoid GN generallyrespond poorly to corticosteroids and cytotoxic drugs,those of other monoclonal Ig deposition diseases, such

as AL-amyloidosis and LCDD [36, 37]. Studies of Ig at with an incidence of ESRD of 50% [3, 12, 13, 18, 20].However, our results demonstrate that aggressive treat-the cell level seem to be essential in immunotactoid GN

as, in two patients with no significant serum paraprotein- ment may lead to NS remission in many patients withthe microtubular pattern. This may have a favorable in-emia, we identified a monotypic population of circulat-

ing lymphocytes expressing a monoclonal Ig identical fluence on the long-term renal prognosis of these pa-tients, as suggested in a previous study [13]. We haveto that of the glomerular microtubular deposits. This led

to a diagnosis of latent B-cell lymphoma in patient 7, coined the term “GOMMID” (for glomerulonephritiswith organized microtubular monoclonal immunoglobu-who had normal blood lymphocyte counts. In patients

with lymphoproliferative disease, the detection of lym- lin deposits) for cases of immunotactoid GN with mono-typic IgG deposits [14, 48]. GOMMID with a microtu-phocyte crystal-like inclusions containing monoclonal Ig

with, in most cases, the same subclass and light chain bule diameter around 15 nm, which is probably animportant component of immunotactoid GN, is associ-type as those of glomerular deposits, may shed light

on the pathogenetic mechanisms of immunotactoid GN. ated with overt or latent lymphoproliferative disease andmay be improved by chemotherapy or autologous bloodCrystal-like inclusions of similar appearance are rarely

described in CLL. They are contained in rough endoplas- stem cell transplantation.


with organized deposits: A new clinicopathological entity? Light,ACKNOWLEDGMENTSelectron-microscopic and immunofluorescence study of 12 cases.

This work was supported by a grant from AREN Poitou-Charentes. Am J Nephrol 10:21–30, 1990Parts of this study were presented at the XVth International Congress 8. Esparza AR, Chazan JA, Nayak RN, Cavallo T: Fibrillaryof Nephrology, Buenos Aires, Argentina, May 2-6, 1999. (immunotactoid) glomerulopathy. A possible role for kappa light

We are greatly indebted to our colleagues for clinical observations, chain in its etiology and/or pathogenesis. Am J Surg Pathol 15:kidney biopsies, serum and urine samples: patients 1 and 13, L. Yver 632–643, 1991(Service de Nephrologie, Angouleme, France); patient 2, J.F. Pouget- 9. Casanova S, Donini U, Zucchelli P, et al: ImmunohistochemicalAbadie and D. Picaud (Services de Medecine Interne et de Nephrologie, distinction between amyloidosis and fibrillar glomerulopathy. AmNiort, France); patient 6, C. Jolimoy, D. Chevet, and E. Justrabo (Ser- J Clin Pathol 97:787–795, 1992vice de Nephrologie, Dijon, France); patient 7, D. Bernon (Service de 10. Alpers CE: Immunotactoid (microtubular) glomerulopathy: AnNephrologie, La Rochelle, France); patient 8, P. Bataille (Service de entity distinct from fibrillary glomerulonephritis? Am J KidneyNephrologie, Boulogne-sur-Mer, France) and A. Marie (Laboratoire Dis 19:185–191, 1992d’Anatomie Pathologique, Amiens, France); patient 9, J.P. Grunfeld, 11. Yang GCH, Nieto R, Stachura I, Gallo GR: UltrastructuralD. Chauveau and L.H. Noel (Service de Nephrologie and Laboratoire immunohistochemical localization of polyclonal IgG, C3, and amy-d’Anatomie Pathologique, Necker Hospital, Paris, France); patient 10, loid P component on the Congo Red-negative amyloid-like fibrilsA. Nony and A. Talin d’Eyzac (Service de Nephrologie, Bourges, of fibrillary glomerulopathy. Am J Pathol 141:409–419, 1992France); patient 11, A. Guerraoui (Service de Nephrologie, Bois-Guil- 12. Iskandar SS, Falk RJ, Jennette JC: Clinical and pathologic fea-laume, France) and A. Francois (Laboratoire d’Anatomie Pathologique, tures of fibrillary glomerulonephritis. Kidney Int 42:1401–1407, 1992Rouen, France); patient 12, L. Frimat and J. Champigneulle (Service 13. Fogo A, Qureshi N, Horn RG: Morphologic and clinical featuresde Nephrologie and Laboratoire d’Anatomie Pathologique, Nancy, of fibrillary glomerulonephritis versus immunotactoid glomerulo-France); patients 14, 17, and 18, M. Baron and D. Picaud (Service de pathy. Am J Kidney Dis 22:367–377, 1993Nephrologie, Niort, France); patient 16, B. Hurault de Ligny and J. C. 14. Touchard G, Bauwens M, Goujon JM, et al: GlomerulonephritisMandard (Service de Nephrologie and Laboratoire d’Anatomie Patho- with organized microtubular monoclonal immunoglobulin depos-logique, Caen, France); patient 20, A. Caillette-Baudouin and B. its. Adv Nephrol Necker Hosp 23:149–175, 1994McGregor (Service de Nephrologie and Laboratoire d’Anatomie Patho- 15. Pronovost PH, Brady HR, Gunning ME, et al: Clinical features,logique, CHU Lyon, France); patient 21, J.D. Gheerbrant, P. Hardy predictors of disease progression and results of renal transplanta-(Service de Nephrologie, Arras, France) and A. Marie; patient 22, H. tion in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Trans-My (Service de Nephrologie, Saint Joseph et Saint Luc, Lyon, France) plant 11:837–842, 1996and B. McGregor; patient 23, M. Beruard (Service de Nephrologie, 16. Coroneos E, Truong L, Olivero J: Fibrillary glomerulonephritisVilleurbanne, France) and B. McGregor. We would also like to thank associated with hepatitis C viral infection. Am J Kidney Dis 29:132–A. Brizard for reviewing hematological data, B. Fernandez and N. 135, 1997Quellard for expert technical assistance. We thank S. Kaveri and J. 17. Markowitz GS, Cheng JT, Colvin RT, et al: Hepatitis C viralSappa (Alex Edelman & Associates) for revising the English usage. infection is associated with fibrillary glomerulonephritis and immu-

notactoid glomerulopathy. J Am Soc Nephrol 9:2244–2252, 1998Reprint requests to Frank Bridoux, M.D., Service de Nephrologie,18. Korbet SM, Schwartz MM, Lewis EJ: Immunotactoid glomerulo-Hopital Jean Bernard, Rue de la Miletrie, BP 577, 86021 Poitiers, France.

pathy. Am J Kidney Dis 17:247–257, 1991E-mail: [email protected]. Jennette JC, Iskandar SS, Falk RJ: Fibrillary glomerulonephri-

tis, in Renal Pathology: With Clinical and Functional Correlations(vol 1, 2nd ed), edited by Tisher CG, Brenner BM, Philadelphia,

APPENDIX JB Lippincott, 1994, pp 553–56320. Brady HR: Fibrillary glomerulopathy. Kidney Int 53:1421–1429, 1998Abbreviations used in this article are: cIg, cytoplasmic immunoglob-21. van Ginneken EEM, Assmann KJM, Koolen MI, et al: Fibrillary-ulins; CLL, chronic B-lymphocytic leukemia; ELISA, enzyme-linked

immunotactoid glomerulopathy with renal deposits of IgA�: Aimmunosorbent assay; EM, electron microscopy; FGN, fibrillary glo-rare cause of glomerulonephritis. Clin Nephrol 52:383–389, 1999merulonephritis; GBM, glomerular basement membrane; GN, glomer-

22. King JAC, Culpepper RM, Corey GR, et al: Glomerulopathiesulonephritis; GOMMID, glomerulonephritis with organized microtu-with fibrillary deposits. Ultrastruct Pathol 24:15–21, 2000bular monoclonal deposits; HBV, hepatitis B virus; HCV, hepatitis C

23. Haas MH, Nair R, Kovesdy C: Renal biopsy teaching case. Avirus; IEL, immunoelectrophoretic; IF, immunofluorescence; Ig, immu-49-year-old woman with hematuria, proteinuria, and glomerularnoglobulin; IT/MTGN, immunotactoid (microtubular) glomerulone-immune complex deposits containing IgA and IgG. Am J Kidneyphritis; LCDD, light chain deposition disease; mAb, monoclonal anti-Dis 36:1281–1285, 2000body; MGUS, monoclonal gammapathy of undetermined significance;

24. Moulin B, Ronco PM, Mougenot B, et al: GlomerulonephritisNS, nephrotic syndrome; PBL, peripheral blood lymphocytes; PCR,in chronic lymphocytic leukemia and related B-cell lymphomas.polymerase chain reaction; SCr, serum creatinine; SIg, surface immuno-Kidney Int 42:127–135, 1992globulins.

25. Cheson BD, Bennett JM, Grever M, et al: National Cancer Insti-tute-sponsored working group guidelines for chronic lymphocytic

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