913 @ 1990 The Japanese Society of Pathology
Case ReDorts
Micro lamella r Structures in Lo bula r Glo meru lonephrit is Associated with Monoclonal IgG Lambda Pa raproteinemia A Case Report and Review of the Literature
Kensuke Joh', Shigeo Aizawa', Takamune Takahashi', Makio Hatakeyama2, Shigeaki Muto3, Yasushi Asano3, Hideo Shirnizu4, and Ryoji Suzuki5
We report a 49-year-old woman who developed lobular glomerulonephritis with prevalent deposition of material positive for IgG, C,, and lambda light chain, but which was not stained by Congo red. Glomeruli revealed massive electron-dense deposits with a microlamellar structure i n the mesangial matrix and peripheral capillary loops. Clinically, the patient had nephrotic syndrome, microhematuria and hypertension. No Bence-Jones protein or cryoglobulin was found in the urine or serum. Anti-DNA antibody was positive, but systemic lupus erythematosus (SLE) was ruled out by repeated serological examinations. lmmunoelectrophoresis of blood and urine revealed increased HgG-lambda paraprotein, but no free light chains were found. We reviewed 5 4 cases reported in the literature, which showed organized crystalline structures on ultrastructural examination, but were unassociated with amyloidosis, SLE, cryoglobulinemia or multiple myeloma. The present patient i s the first reported to have exhibited a combination of glomerulonephritis with organized deposits, monoclonal IgG lambda paraproteinemia, and the presence of anti-DNA antibody. Acta Pathol Jpn 40: 913-921, 1990. Key words : Glomerulonephritis, Organized dense deposits, Paraproteinemia
Received July 3, 1990. Accepted for publication September 10, 1990. 'Department of Pathology, The Jikei University School of Medicine, Tokyo. ZDepartment of Allergy and Collagen Disease, 3Departmentof Nephrology, and 4Departmentof Pathology, Jichi Medical School, Tochigi. 5Department of Urology, Mito Red Cross Hospital, Mito. DepartMailing address: Kensuke Joh, M.D. (j& E&$), ment of Pathology, The Jikei University School of Medicine, 3-25-8, IViishishinbashi, Minato-ku, Tokyo 105, Japan.
INTRODUCTION There have been a few reports of glomerulopathies associated with deposition of peculiar and highly organized crystalline structures. These lesions are distinct from those seen in systemic lupus erythematosus (SLE), amyloidosis and cryoglobulinemia. However, this disease entity has not yet been well established because its clinical features, the underlying disease, and the morphology of the crystalloid structures vary from case t o case. This condition has been given various names, such as immunotactoid glomerulopathy ( l ) , glomerulonephritis with organized deposits (2), glomerulopathy with giant fibrillary deposits (3), Congo red-negative amyloid-like glomerulopathy (4), fingerprint-like straight crystalloid microfila ments in lobular glomeru lonephrit is (5), fi brilla ry g lomerulonephrit is (6), g lomerulo pat hy with a my lo id stain-negative microfibrillary deposits (7), atypical membranous glomerulonephritis with fibrillary subepithelial deposits (8, 9), and tubular microfibril deposition in the glomeruli of membranous nephropathy (10). The paucity of information on the clinical course and pathological findings associated with this condition prompted us to report a recent case, together with a review of the previous Iitera t ure.
CLINICAL SUMMARY The patient was a 49-year-old woman who had been admitted to the Mito Red Cross Hospital in lbaragi prefecture for evaluation of hypertension, microscopic hematuria and nephrotic syndrome. Edema of the bilateral lower legs but not the face had developed 4 months prior to admission. The patient's weight had increased
914
Organized Dense Deposits (Joh et a/.)
about 10 kg after she had developed common cold-like symptoms one month prior to admission. Medical history included hysterectomy for a uterine myoma without blood transfusion at the age of 34 years. There was a
positive family history of hypertension, and s h e herself had been hypertensive for 25 years. The hypertension (210/100 mmHg) had been treated since the alge of 45 years. On admission, the patient was 1 5 9 cni in height
Figure 1. Glomeruli from t i e present patient are enlarged and show mesangial hypercellularity and nodular sclet'osis exten ding to the periphery, where the glomerular basement membrane has become thickened and locally duplicated Capillaries are com pressed to the periphery, ha\e narrowed lumina, and show marked rieutrophilic infiltration (Periodic acid mettienamine sil ver stain)
Figure2. Diffuse and strong staining for IgG, C,, and lambda light chain is evident in mesangial nodules and along capillaries ( a : anti IgG antibody). IgM, IgA and C, show a diffuse and granular pattern of staining mainly along the peripheral capillary loops ( b . anti-lgM antibody).
Acta Pathologica Japonica 40 (12): 1990
and 7 5 k g in weight. Her blood pressure was 185/100 mmHg (serum renin: 1.02 nglml, serum aldosterone: 0.5 ng/dl). Physical examination revealed marked pitting edema of the lower extremities. A chest roentgenogram showed cardiomegaly and bilateral pleural effusion. The hematological findings were as follows : white cell count, 6,900/mm3 with a normal differential count ; hemoglobin, 14.8 g/dl ; hematocrit, 43.5%. Laboratory studies revealed evidence of nephrotic syndrome without renal insufficiency. Urinalysis showed proteinuria (5 g/day), but Bence-Jones protein was negative. The urinary sediment contained 5-6 red blood cells and 6-7 white blood cells per high-power field, as well as oval fat bodies and hyaline, fatty, cellular and granular casts. Serum total protein was 5.1 g/dl (albumin, 63.5%; beta-1-globulin, 6.0% ; beta-2-globulin, 10.0% ; gamma--globulin, 11.9% ; M-protein, 11.1%). Blood urea nitrogen (BUN) was 21 mg/dl, serum creatinine was 1.1 mg/dl, and creatinine clearance was 90-100 liter/day. Results of various other examinations were either normal or negative, including rheumatoid factor,
915
ASOT, antinuclear factor, Coombs’ test, LE cells, and complement (CH,,, 24.8 U/ml; C, 7 9 mg/dl; C,, 35 mg/dl). Cryoglobulin was not detected in the urine or serum after several examinations. Immunoelectrophoresis of blood and urine revealed an excess of IgG-lambda paraprotein, but no free light chains were seen. AntiDNA antibody was positive (18.6 U/ml-RIA). The possibility of membranoproliferative glomerulonephritis due to SLE was ruled out by repeated examinations, which showed no leukopenia, no LE cells, and negative antinuclear factor, and by the absence of any history of photosensitivity. The patient was treated with steroid pulse therapy and showed a good response, proteinuria being reduced to 1 g/day. She was discharged with continuous followup, and was maintained on prednisolone at 1 5 mg/day. No Bence-Jones protein or cryoglobulin was detected in repeated examinations. Two years after the initial hospitalization, she was admitted again to the hospital of Jichi Medical School in Tochigi prefecture with a relapse of nephrotic syndrome. She showed severe proteinuria
Figure 3. Electron micrograph of nodules in the glomerular tufts shows aggregated deposits possessing a unique structure. The peripheral capillaries have almost been obliterated in area of marked neutrophiltc and macrophagic infiltration ( x 2,800)
916
Organized Dense Deposits (Joh et a / . )
(15 g/day) and elevation of the serum creatinine level to 4.9 mg/dl (BUN 65 mg/dl, uric acid 4.2 mg/dl). Mprotein was 20% of the total serum protein level of 6.2 mg/dl. Hypocomplementemia (C3,11 mg/dl ; C,, 4 mg/dl) was observed once during her follow-up examinations.
MATERIALS AND METHODS The first and second renal biopsies were performed at Mito Red Cross Hospital and Jichi Medical School Hospital, respectively. For light microscopy, tissue was fixed in 0.1 M phosphate-buffered 10% formalin. Paraffin
Figure 4. The deposits are present in almost all parts of the mesangial matrix and extend to the subendothelial space (~9,100).
Acta Pathologica Japonica 40 ( 1 2 ) : 1990
sections (3 p m thick) were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, and periodic acid-methenamine silver. For electron microscopy, kidney tissue was fixed in phosphatebuffered 1.2% glutaraldehyde, post-fixed in 1%osmium tetroxide, and embedded in Epon 812. Ultrathin sections were double-stained with uranyl acetate and lead cit ra t e. For immuno histoc hemica I studies, pa raff i n-embedded sections were processed by the peroxidaseantiperoxidase method. Antisera against IgG, IgM, IgA, C,,C,, and kappa and lambda light chains (DAKO, Santa Barbara. CA, USA) were used to treat the sections after digestion for 15 min at 37°C by 0.05% protease type 8 (Sigma, St. Louis, MO, USA).
917
PATHOLOGICAL FINDINGS The first biopsy specimen was taken mainly from the renal cortex and included 25 glomeruli. There were 5 glomeruli with adhesions, 2 with small cellular crescents, and one with periglomerular fibrosis. The other 17 glomeruli were enlarged ( 3 2 0 k 2 9 p m in diameter) showing lobular accentuation due to mesangial hypercellularity and nodular mesangial sclerosis; these were PAS-positive and did not stain with Congo red. The mesangial area with nodular sclerosis extended to the periphery, where the glomerular basement membrane had become thickened and locally duplicated. Glomerular capillaries were compressed to the periphery, had narrowed lumina, and showed marked neutrophilic
Figure 5. Deposits composed of arrays of cisternal, serpiginously curvilinear, lamellar structures 25 n m wide arranged in parallel with a periodicity of 5 0 nm ( ~ 3 5 , 0 0 0 ) .
918
Organized Dense Deposits (Joh et a/.) Table 1. Clinical
Author Korbet (1) Mazzucco (2) Duffy (13) Alpers (6) Burgin (3) Sturgill (4) Rosenmann (8,9) Olesnicky (10) Hamaya (5) Schifferli (14) Griffel (12) Kobayashi (7) Cadnapaphornchai (15) Present case Total
No of pts. 11 12 8 7 4 3 2 2
37/18
55
age from/to 25/59 10154 26/64 19/80 33/44 39/62 45/61 29/72 64 61 47 44 45 49 10180
hyptn.
cryoglob.
___.-
9/11 7/12 318 417 214 213 012 112 111 111 111
111 33/55 (60%)
39/44 (89%)
011 111 31155(56%)
019 0110 014 017 013 112 012 012 011 011 011 011 011 011 1/53 (2%)
PU, proteinuria ; NS, nephrotic syndrome (PU > 3 g/day) ; ANF, antinuclear antibody ; NL, normal; L, lower; NA, not available; PRI, progressive renal insufficiency ( + ; creatinipe clearance of less than 70 ml/min) ; CLL, chronic lymphocytic leukemia ; MCTD, mixed connective tissue disease; TB, tuberculosis ; OS, otosclerosis ; FG, familial glomerulopathy ; ML, malig-
along the fringes of peripheral capillary loops (,Fig. 2b). Kappa light chain was focally and segmentally positive along the peripheral capillaries. Electron microscopy showed that the markedly wide mesangial matrix was composed of aggregated deposits with a unique structure extending almost into the subendothelial space of the capillary loop (Figs. 3, 4). These structures were found in almost all parts of the deposits. There were neither amorphous dense deposits nor viruslike particles suggestive of lupus nephritis. The
infiltration with swollen endothelial cells (Fig. 1). Afferent and efferent arterioles were not obviously hyalinized. Tubules showed mild focal atrophy (10-15% of the total field) and were surrounded by interstitial fibrosis with mild infiltration of lymphocytes and eosinophils. lmmunohistochemical studies revealed diffuse and strong staining for IgG, C,, and lambda light chain, both in the extended mesangial nodules and along the capillaries (Fig. 2a). IgM, IgA, and C, showed a diffuse and granular pattern of staining, which extended mainly
Table 2.
Author Korbet (1) Mazzucco (2)
DPGN
2/11 5/12
Duffy (13) Alpers (6) Burgin (3) Sturgill (4) Rosenmann (8, 9)
-
MGN -
3/12
MPGN
IgG
IgA
IgM
c3
Morphological
c4
Clq
9/11 4/12
11/11 10112
2/11 4/12
7/11 7/12
11/11 12/12
ND 3/6
8/11 12/12
7/7 6/7 013 2/3 2/2
317 017 1/ 3 1/3 0/2
4/7 7/7 1 /3 1/3 1/2
7/7 NA 0/3 3/3 1 /2
3/3 NA 113 0/1 NA
3/3 NA NA 2/3 NA
-
-
-
1/2
8/8 7/7 4/4 3/3 1/2
Olesnicky (10)
-
2/2
-
2/2
1/2
1/2
212
NA
2/2
Hamaya (5) Schifferli (14) Griffel (12)
-
-
1/1 1/1
1/1 1/1 1/1 1/1 1/1 1/1 46/53 (87%)
1/1 0/1 0/1 111 0/1 1/I 15/53 (28%)
0/1 1/I 1/1 0/1 0/1 1/1 26/53 (49%)
0/1
-
0/1 1 /I NA NA NA NA 9/15 (60%)
0/1 NA NA 1 /1 NA 1/I -___ 30/34 (88%)
Kobayashi (7) CadnaoaDhornchai (151 . . . , Present case Total
-
1/1
-
-
-
-
-
-
-
8/55 (15%)
7/55 (13%)
1/1 1/1 40/55 (73%)
1/1
1 /1 1/1 1/1 NA 111 41/45 (91%)
NA, not available; US, ultrastructure; RA, random arrangement; OA, orderly arrangement; pd, periodicity; MT, microtubular; MF, microfibrillary ; GF, granulated filament ; LS, lamellar structure. -, all negative.
919
Acta Pathologica Japonica 40 (12) : 1990 Findings paraprot.
~~~~~
0111 NA 017 NA NA 011 012 012 NA 011 NA 011 011 011 0127
(0%)
NA
-
+
NA
NA NA
NA
-
+ +
9/35 (26%)
ANA
319 0112 318 017 214 313
212 NA
011 011 NA 011 011 011 13/50 (26%)
yik
C3 NL/L
Clq/C4 NL/L
+/-
PRI
references
NA 015 NA NA NA NA NA NA NA 011 NA NA 011 111 118 (13%)
1110 1210 NA NA
1110 1111 NA NA 311 NA 1I 0 210 NA 1I 0 1I 0 1I 0 1I 0 1I 0 2/35 (6%)
615 2110 414 512 113 211 1I 1 012 1I 0 1I 0 o/ 1 1I 0 1I 0 1I 0 26/55 (47%)
CLL 1/11, MCTD 1/11
310 4/0 1I 0
2/o 1I 0 011 1I 0 1I 0 1I 0 011 2/39 (5%)
nant lymphoma ; LCD, light-chain disease; ATA, antithyroglobulin crosornal antibody ; BMG, benign monoclonal gammopathy. positive in serum imrnunoelectrophoresis ; -, negative.
LCD 717
0s 114, FG 414 RA 113 M L 112 T B 111
ATA 111, AMA 111 BMG 111 BMG 111
antibody; AMA,
antirni
+,
deposits comprised arrays of cisternal, serpiginously curvilinear, lamellar structures measuring 25 nm in width that were arranged in parallel with a periodicity of 5 0 nm (Fig. 5). The peripheral capillaries were almost obliterated in areas of marked neutrophilic and macrophagic infiltration. The macrophages had numerous enlarged lysosomes showing no microlamellar structure (Fig. 3). The mesangial cells were moderately proliferated without any particular abnormality (Fig. 4). The foot processes of the epithelial cells showed diffuse effacement. There
Finding j lambda
Us
6/6 9/9
3,'6 8/9
5/5 7/7 NA 1/2 1/1
5/5 117 NA 1/2 0/1
MT MF MT MF MF GF MF MF
NA
NA
MF
kappa ~-
0/1 0/1 NA NA NA NA 1/1 1/1 1/ I 0/1 1/I 0/1 ____ 30/34 24/34 (88%) (71%) ____-
MT MF MT MF MT ML
width/pd (nm) 27/27 11-30 20-35 20 10-19.5 12 7.5-10 10 25/10 8-12 18-22 10/25 >9 20/20 15-20 10-20 25/50
RA/OA OA RA 9/12 OA 3/12 RA RA RA RA RA OA RA OA OA OA RA OA OA
were neither organized deposits nor amorphous dense deposits on the tubular basement membrane. The second renal biopsy was performed at the Jichi Medical School Hospital two years after the initial hospitalization. The kidney tissue included 10 glomeruli. There were 2 glomeruli with adhesion and one with a small cellular crescent. All 10 glomeruli were slightly enlarged, but the glomerular size was reduced in comparison with the first biopsy (230+15 p m in diameter). The glomeruli still showed lobular accentuation due to mesangial hypercellularity, although nodular sclerotic lesions had become less apparent. Tubular atrophy and interstitial fibrosis with focal lymphocytic infiltration were seen ( 2 5 3 0 % of the total field).
DISCUSSION We have reported a patient who had a rare combination of lobular glomerulonephritis with microlamellar organized deposits, benign monoclonal IgG lambda paraproteinemia, and the appearance of anti-DNA antibody. The patient exhibited all the typical features of the newly described g lo merulo pat hy, immu nota ctoid g lomerulopathy (1). First, the clinical triad of severe hypertension, proteinuria and microscopic hematuria was followed by declining renal function over a period of 3 years. Second, histological studies showed mesa ngia I expansion and prominent deposition of extracellular crystalline structures in the mesangial matrix and capillary loops, which appeared not to be amyloid but rather composed of various immunoglobulins and complement. Third, the possibility of underlying SLE was ruled out by repeated
920
Organized Dense Deposits (Joh et a/.)
serological examinations. Unusually, our patient showed benign monoclonal gammopathy (IgG lambda paraproteinemia), whereas Korbet et a/. (1) were unable to find any paraproteinemia in either 9 patients examined by serum protein electrophoresis or 5 patients who underwent urinary immunoelectrophoresis. Anti-DNA antibody, which was not examined by Korbet et a/., was positive in our patient. Prominent neutrophilic infiltration of the glomeruli with swollen endothelial cells was associated with hypocomplementemia in our patient, whereas neither a cellular inflammatory reaction nor a decrease in the serum complement level was reported by Korbet et a/. in 11 patients. Electron-dense deposits showed a microlamellar structure in the present case, whereas a microtubular structure was seen by Korbet et a/. These discrepancies prompted us t o review previous similar reports. We found 5 5 cases in the literature which showed ultrastructural evidence of organized crystalline structures which were not caused by amyloidosis, SLE, cryoglobulinemia (except for one of 3 cases reported by Sturgill et a/. (4)) or multiple myeloma (Tables 1 and 2) (1-15). The patients comprised 18 females and 3 7 males with an age range of 10-80 years. Proteinuria was a common feature in all 5 5 patients. In 3 3 of them (60%), proteiuria reached the nephrotic level (3.0 g/ day). Microhematuria was seen in 3 9 out of 44 patients (89%), and hypertension was found in 31 out of 5 5 patients (56%). Decreased levels of C, and C,,/C, were seen in 2 out of 3 9 patients (5%) and in 2 out of 3 5 patients (6%), respectively. Renal dysfunction with a creatinine clearance of less than 7 0 ml/min was seen in 26 of the 55 cases (47%). None of 2 7 cases studied had Bence-Jones proteinuria. Paraprotein was found in 9 out of 3 5 patients, 7 of whom had light-chain disease (IgG kappa type) (6) whereas the patient reported by Cadnapaphornchai and Sillix (15) and the present patient had IgG lambda paraproteinemia. Antinuclear antibody was positive in 13 out of 50 cases (26%), but anti-DNA antibody was found only in the present case. One of 5 3 patients studied (2%) exhibited cryoglobulinemia. Six patients had underlying diseases including chronic lymphocytic leukemia, mixed connective tissue disease, tuberculosis, otosclerosis, malignant lymphoma, hyperthyroidism, and benign monoclonal gammopathy. Characteristic morphological findings in the reported cases are shown in Table 2. No morphological descrip tions based on light microscopy were explicitly mentioned in some reports. Mesangial hypercellularity and nodular formation appeared to be proportional to the severity of the disease process. The degree of involvement of the glomerular capillary wall seemed to vary in each case from a pattern resembling membranoprolifer-
ative glomerulonephritis (MPGN) to one resembling membranous glomerulonephritis (MGN). In the cases which resembled diffuse mesangioproliferati\e, glomerulonephritis (DPGN), the deposits in the gliomerular basement membrane were rather inconspicuous by light microscopy. Light microscopy demonstrate0 DPGN in 8 cases (15%), MGN in 7 cases (13%) and MPGN in 40 cases (73%). The cases showing a MPGNi pattern rarely had acute lesions or hypocomplementemia. There were only 6 MPGN cases: the present one, the case reported by Cadnapaphornchai and Sillix (15), the case reported by Hamaya and Doi (5), and 3 cases described by Mazzucco et a/. (2), in which acute lesions with leukocytic infiltration and endothelial swelling were present. lmmunofluorescence studies showed that thle lesions contained various immunoglobulin isotypes, complement and light chains. Components of IgG, Cs, C,, and kappa light chain were frequently positive in 46 out of 5 3 cases (87%), 41 out of 4 5 cases (91%), 3 0 out of 3 4 cases (88%) and 30 out of 3 4 cases (8893, respectively. IgM and lambda light chain were positive in 2 6 3ut of 5 3 cases (49%) and in 2 4 out of 34 cases (71%). IgA was positive in 15 out of 5 3 cases (28%). Except for the 6 out of 7 cases of light-chain disease (5) and the 2 cases of benign monoclonal gammopathy (15), kappa and lambda light chains were both positive. Electron microscopy revealed crystalloid structures 10-35 nm wide in the mesangium and glomerular capillary loops. These crystalline structures were sometimes microtubular or microlamellar, and sometimes microfibrillar or in the form of granulated filaments. The former group had electron-lucent central cores in crosssection, and most of the microtubular structures (except those in Schifferi’s case) exhibited orderly deposition of parallel microtubule arrays with a certain periodicity. The microtubules were of various widths : 3 5 rim, 27 nm, 25 nm, 2 0 nm and 10 nm. The latter showed a crisscross arrangement or contained randomly arranged nont ubula r and branching microfibrilla ry st ruct uri:s. These structures had thinner components than the first group, measuring 3 0 nm, 2 0 nm, 18 nm, 1 5 nm, 1 2 nm, 11 nm and 10 nm. All these crystalline structures h,ad microfibrils more than 9 nm wide, and thus could be differentiated from amyloidosis, in which thick-walled microfibrils measuring 9 nm in diameter are seen. Although the deposits were immunologically and morphologically similar to some deposits reported in cryoglobulinemia (161, the serum of the reported patients contained no cryoglobulin. The microtubular or microfibrillary structures reported differed from the lesions of cryoglobulinemia, which de onstrate paired annuilar structures or curved cylinders separated by an electron-lucent space (16). The presence of extracellular fibrilllary mate-
P
Acta Pathologica Japoriica 40 (12) : 1990
rials has been observed in a wide variety of glomerulopathies (17). Most often these materials represented collagen, fibrin, o r commonly observed components of the glomerula r basement membrane o r mesa ngia I matrix. However, immunofluorescence studies indicate a different origin f o r the fibrillary material in this condition. No plausible mechanism for the genesis of these specific microfibrils has yet been proved. Korbet et a/. (1) speculated that the glomerular deposition of fibrils could be related t o a high concentration of plasma proteins in the glomeruli, but it is unclear what physicochemical mechanism would induce these so-called i m munotactoids t o form. Schifferli et a/. (14) suggested that the disease might be related to the deposition of circulating insoluble immune complexes in both skin and glomeruli, followed by their crystallization. Cadnapaphornchai and Sillix (15) also documented the recurrence of organized dense deposits in the renal allograft i n the patient with IgG lambda monoclonal gammopathy. When the deposits are composed of uniform subcomponents having strong intermolecular attraction, it is possible that abnormal production of monoclonal immunoglobulins, like that seen in the present case, would help t o induce these lesions.
REFERENCES Korbet SM, Schwartz MM, Rosenberg BF, et a/. Immunota cto id g lo merulo pat hy. Medicine (Ba Itimo re) 60 : 228-243, 1985. h4azzucco G, Casanova S, Donini U, et a/. Glomerulonephritis with organized deposits : A new clinicopathological entity ? Light-, electron-microscopic and immunofluorescence study of 12 cases. Am J Nephrol 10: 21-30, 1990. Eurgin M, Hofmann E, Reutter FW, e t a/. Familial glomerulopathy with giant fibrillar deposits. Virchows Arch [A] 388: 313-326, 1980. S,turgill BC, BoIton WK, and Griffith KM. Congo red-
5. 6.
7. 8.
9. 10.
11. 12.
13. 14.
15. 16.
17.
92 1
negative amyloidosis-like glomerulopathy. Hum Pathol 1 6 : 220-224, 1985. Hamaya K and Doi K. Fingerprint-like straight crystalloid microfilaments in lobular glomerulonephritis. Acta Pathol Jpn 3 5 : 767-773, 1985. Alpers CE, Rennke HG, Hopper J Jr, and Biava CG. Fibrillary glomerulonephritis : An entity with unusual immunofluorescence features. Kidney Int 3 1 : 781 789, 1987. Kobayashi Y, Fujii K, Kurokawa A, et a/. Glomerulopathy with amyloid-stain-negative microfibrillar glomerular deposits. Nephron 48 : 33-39, 1988. Rosenmann E. Brisson ML, Bercovitch DD, and Rosenberg A. Atypical membranous glomerulonephritis with fibrillar subepithelial deposits in a patient with malignant lymphoma. Nephron 48: 226-230, 1988. Rosenmann E and Eliakim M. Nephrotic syndrome associated amyloid-like glomerular deposits. Nephron 18: 301-308, 1977. Olesnicky L, Doty SB, Bartani T, and Pirani CL. Tubular microfibrils in the glomeruli of membranous nephropathy. Arch Pathol Lab Med 108: 902-905, 1984. Schwartz MM and Lewis EJ. The quarterly case: Nephrotic syndrome in a middle-aged man. Ultrastruct Pathol 1 : 575-582, 1980. Griffel B and Bernheim J. Glomerular deposits in idiopathic membranous glomerulopathy. Arch Pathol Lab Med 1 0 4 : 56-57, 1980. Duffy JL, Khurana E, Susin M, et a/. Fibrillary renal deposits and nephritis. Am J Pathol 1 1 3 : 279-290, 1983. Schifferli JA, Merot Y, Cruchaud A, and Chatelanat F. lmmunotactoid glomerulopathy with leukocytoclastic skin vasculitis and hypocomplementemia : A case report. Clin Nephrol 2 7 : 151-155, 1987. Cadnapaphornchai P and Sillix D. Recurrence of monoclonal gammopathy-related glomerulonephritis in renal allograft. Clin Nephrol 31 : 156-159, 1989. Feiner H and Gallo G. Ultrastructure in glomerulonephritis associated with cryoglobulinemia. A report of six cases and review of the literature. Am J Pathot 88: 145-162, 1977. Duffy JL and Churg J. Extracellular fibrils in the renal glomerulus. Ultrastruct Pathol 6 : iii-vi, 1984.
Case ReDorts
Micro lamella r Structures in Lo bula r Glo meru lonephrit is Associated with Monoclonal IgG Lambda Pa raproteinemia A Case Report and Review of the Literature
Kensuke Joh', Shigeo Aizawa', Takamune Takahashi', Makio Hatakeyama2, Shigeaki Muto3, Yasushi Asano3, Hideo Shirnizu4, and Ryoji Suzuki5
We report a 49-year-old woman who developed lobular glomerulonephritis with prevalent deposition of material positive for IgG, C,, and lambda light chain, but which was not stained by Congo red. Glomeruli revealed massive electron-dense deposits with a microlamellar structure i n the mesangial matrix and peripheral capillary loops. Clinically, the patient had nephrotic syndrome, microhematuria and hypertension. No Bence-Jones protein or cryoglobulin was found in the urine or serum. Anti-DNA antibody was positive, but systemic lupus erythematosus (SLE) was ruled out by repeated serological examinations. lmmunoelectrophoresis of blood and urine revealed increased HgG-lambda paraprotein, but no free light chains were found. We reviewed 5 4 cases reported in the literature, which showed organized crystalline structures on ultrastructural examination, but were unassociated with amyloidosis, SLE, cryoglobulinemia or multiple myeloma. The present patient i s the first reported to have exhibited a combination of glomerulonephritis with organized deposits, monoclonal IgG lambda paraproteinemia, and the presence of anti-DNA antibody. Acta Pathol Jpn 40: 913-921, 1990. Key words : Glomerulonephritis, Organized dense deposits, Paraproteinemia
Received July 3, 1990. Accepted for publication September 10, 1990. 'Department of Pathology, The Jikei University School of Medicine, Tokyo. ZDepartment of Allergy and Collagen Disease, 3Departmentof Nephrology, and 4Departmentof Pathology, Jichi Medical School, Tochigi. 5Department of Urology, Mito Red Cross Hospital, Mito. DepartMailing address: Kensuke Joh, M.D. (j& E&$), ment of Pathology, The Jikei University School of Medicine, 3-25-8, IViishishinbashi, Minato-ku, Tokyo 105, Japan.
INTRODUCTION There have been a few reports of glomerulopathies associated with deposition of peculiar and highly organized crystalline structures. These lesions are distinct from those seen in systemic lupus erythematosus (SLE), amyloidosis and cryoglobulinemia. However, this disease entity has not yet been well established because its clinical features, the underlying disease, and the morphology of the crystalloid structures vary from case t o case. This condition has been given various names, such as immunotactoid glomerulopathy ( l ) , glomerulonephritis with organized deposits (2), glomerulopathy with giant fibrillary deposits (3), Congo red-negative amyloid-like glomerulopathy (4), fingerprint-like straight crystalloid microfila ments in lobular glomeru lonephrit is (5), fi brilla ry g lomerulonephrit is (6), g lomerulo pat hy with a my lo id stain-negative microfibrillary deposits (7), atypical membranous glomerulonephritis with fibrillary subepithelial deposits (8, 9), and tubular microfibril deposition in the glomeruli of membranous nephropathy (10). The paucity of information on the clinical course and pathological findings associated with this condition prompted us to report a recent case, together with a review of the previous Iitera t ure.
CLINICAL SUMMARY The patient was a 49-year-old woman who had been admitted to the Mito Red Cross Hospital in lbaragi prefecture for evaluation of hypertension, microscopic hematuria and nephrotic syndrome. Edema of the bilateral lower legs but not the face had developed 4 months prior to admission. The patient's weight had increased
914
Organized Dense Deposits (Joh et a/.)
about 10 kg after she had developed common cold-like symptoms one month prior to admission. Medical history included hysterectomy for a uterine myoma without blood transfusion at the age of 34 years. There was a
positive family history of hypertension, and s h e herself had been hypertensive for 25 years. The hypertension (210/100 mmHg) had been treated since the alge of 45 years. On admission, the patient was 1 5 9 cni in height
Figure 1. Glomeruli from t i e present patient are enlarged and show mesangial hypercellularity and nodular sclet'osis exten ding to the periphery, where the glomerular basement membrane has become thickened and locally duplicated Capillaries are com pressed to the periphery, ha\e narrowed lumina, and show marked rieutrophilic infiltration (Periodic acid mettienamine sil ver stain)
Figure2. Diffuse and strong staining for IgG, C,, and lambda light chain is evident in mesangial nodules and along capillaries ( a : anti IgG antibody). IgM, IgA and C, show a diffuse and granular pattern of staining mainly along the peripheral capillary loops ( b . anti-lgM antibody).
Acta Pathologica Japonica 40 (12): 1990
and 7 5 k g in weight. Her blood pressure was 185/100 mmHg (serum renin: 1.02 nglml, serum aldosterone: 0.5 ng/dl). Physical examination revealed marked pitting edema of the lower extremities. A chest roentgenogram showed cardiomegaly and bilateral pleural effusion. The hematological findings were as follows : white cell count, 6,900/mm3 with a normal differential count ; hemoglobin, 14.8 g/dl ; hematocrit, 43.5%. Laboratory studies revealed evidence of nephrotic syndrome without renal insufficiency. Urinalysis showed proteinuria (5 g/day), but Bence-Jones protein was negative. The urinary sediment contained 5-6 red blood cells and 6-7 white blood cells per high-power field, as well as oval fat bodies and hyaline, fatty, cellular and granular casts. Serum total protein was 5.1 g/dl (albumin, 63.5%; beta-1-globulin, 6.0% ; beta-2-globulin, 10.0% ; gamma--globulin, 11.9% ; M-protein, 11.1%). Blood urea nitrogen (BUN) was 21 mg/dl, serum creatinine was 1.1 mg/dl, and creatinine clearance was 90-100 liter/day. Results of various other examinations were either normal or negative, including rheumatoid factor,
915
ASOT, antinuclear factor, Coombs’ test, LE cells, and complement (CH,,, 24.8 U/ml; C, 7 9 mg/dl; C,, 35 mg/dl). Cryoglobulin was not detected in the urine or serum after several examinations. Immunoelectrophoresis of blood and urine revealed an excess of IgG-lambda paraprotein, but no free light chains were seen. AntiDNA antibody was positive (18.6 U/ml-RIA). The possibility of membranoproliferative glomerulonephritis due to SLE was ruled out by repeated examinations, which showed no leukopenia, no LE cells, and negative antinuclear factor, and by the absence of any history of photosensitivity. The patient was treated with steroid pulse therapy and showed a good response, proteinuria being reduced to 1 g/day. She was discharged with continuous followup, and was maintained on prednisolone at 1 5 mg/day. No Bence-Jones protein or cryoglobulin was detected in repeated examinations. Two years after the initial hospitalization, she was admitted again to the hospital of Jichi Medical School in Tochigi prefecture with a relapse of nephrotic syndrome. She showed severe proteinuria
Figure 3. Electron micrograph of nodules in the glomerular tufts shows aggregated deposits possessing a unique structure. The peripheral capillaries have almost been obliterated in area of marked neutrophiltc and macrophagic infiltration ( x 2,800)
916
Organized Dense Deposits (Joh et a / . )
(15 g/day) and elevation of the serum creatinine level to 4.9 mg/dl (BUN 65 mg/dl, uric acid 4.2 mg/dl). Mprotein was 20% of the total serum protein level of 6.2 mg/dl. Hypocomplementemia (C3,11 mg/dl ; C,, 4 mg/dl) was observed once during her follow-up examinations.
MATERIALS AND METHODS The first and second renal biopsies were performed at Mito Red Cross Hospital and Jichi Medical School Hospital, respectively. For light microscopy, tissue was fixed in 0.1 M phosphate-buffered 10% formalin. Paraffin
Figure 4. The deposits are present in almost all parts of the mesangial matrix and extend to the subendothelial space (~9,100).
Acta Pathologica Japonica 40 ( 1 2 ) : 1990
sections (3 p m thick) were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), Masson’s trichrome, and periodic acid-methenamine silver. For electron microscopy, kidney tissue was fixed in phosphatebuffered 1.2% glutaraldehyde, post-fixed in 1%osmium tetroxide, and embedded in Epon 812. Ultrathin sections were double-stained with uranyl acetate and lead cit ra t e. For immuno histoc hemica I studies, pa raff i n-embedded sections were processed by the peroxidaseantiperoxidase method. Antisera against IgG, IgM, IgA, C,,C,, and kappa and lambda light chains (DAKO, Santa Barbara. CA, USA) were used to treat the sections after digestion for 15 min at 37°C by 0.05% protease type 8 (Sigma, St. Louis, MO, USA).
917
PATHOLOGICAL FINDINGS The first biopsy specimen was taken mainly from the renal cortex and included 25 glomeruli. There were 5 glomeruli with adhesions, 2 with small cellular crescents, and one with periglomerular fibrosis. The other 17 glomeruli were enlarged ( 3 2 0 k 2 9 p m in diameter) showing lobular accentuation due to mesangial hypercellularity and nodular mesangial sclerosis; these were PAS-positive and did not stain with Congo red. The mesangial area with nodular sclerosis extended to the periphery, where the glomerular basement membrane had become thickened and locally duplicated. Glomerular capillaries were compressed to the periphery, had narrowed lumina, and showed marked neutrophilic
Figure 5. Deposits composed of arrays of cisternal, serpiginously curvilinear, lamellar structures 25 n m wide arranged in parallel with a periodicity of 5 0 nm ( ~ 3 5 , 0 0 0 ) .
918
Organized Dense Deposits (Joh et a/.) Table 1. Clinical
Author Korbet (1) Mazzucco (2) Duffy (13) Alpers (6) Burgin (3) Sturgill (4) Rosenmann (8,9) Olesnicky (10) Hamaya (5) Schifferli (14) Griffel (12) Kobayashi (7) Cadnapaphornchai (15) Present case Total
No of pts. 11 12 8 7 4 3 2 2
37/18
55
age from/to 25/59 10154 26/64 19/80 33/44 39/62 45/61 29/72 64 61 47 44 45 49 10180
hyptn.
cryoglob.
___.-
9/11 7/12 318 417 214 213 012 112 111 111 111
111 33/55 (60%)
39/44 (89%)
011 111 31155(56%)
019 0110 014 017 013 112 012 012 011 011 011 011 011 011 1/53 (2%)
PU, proteinuria ; NS, nephrotic syndrome (PU > 3 g/day) ; ANF, antinuclear antibody ; NL, normal; L, lower; NA, not available; PRI, progressive renal insufficiency ( + ; creatinipe clearance of less than 70 ml/min) ; CLL, chronic lymphocytic leukemia ; MCTD, mixed connective tissue disease; TB, tuberculosis ; OS, otosclerosis ; FG, familial glomerulopathy ; ML, malig-
along the fringes of peripheral capillary loops (,Fig. 2b). Kappa light chain was focally and segmentally positive along the peripheral capillaries. Electron microscopy showed that the markedly wide mesangial matrix was composed of aggregated deposits with a unique structure extending almost into the subendothelial space of the capillary loop (Figs. 3, 4). These structures were found in almost all parts of the deposits. There were neither amorphous dense deposits nor viruslike particles suggestive of lupus nephritis. The
infiltration with swollen endothelial cells (Fig. 1). Afferent and efferent arterioles were not obviously hyalinized. Tubules showed mild focal atrophy (10-15% of the total field) and were surrounded by interstitial fibrosis with mild infiltration of lymphocytes and eosinophils. lmmunohistochemical studies revealed diffuse and strong staining for IgG, C,, and lambda light chain, both in the extended mesangial nodules and along the capillaries (Fig. 2a). IgM, IgA, and C, showed a diffuse and granular pattern of staining, which extended mainly
Table 2.
Author Korbet (1) Mazzucco (2)
DPGN
2/11 5/12
Duffy (13) Alpers (6) Burgin (3) Sturgill (4) Rosenmann (8, 9)
-
MGN -
3/12
MPGN
IgG
IgA
IgM
c3
Morphological
c4
Clq
9/11 4/12
11/11 10112
2/11 4/12
7/11 7/12
11/11 12/12
ND 3/6
8/11 12/12
7/7 6/7 013 2/3 2/2
317 017 1/ 3 1/3 0/2
4/7 7/7 1 /3 1/3 1/2
7/7 NA 0/3 3/3 1 /2
3/3 NA 113 0/1 NA
3/3 NA NA 2/3 NA
-
-
-
1/2
8/8 7/7 4/4 3/3 1/2
Olesnicky (10)
-
2/2
-
2/2
1/2
1/2
212
NA
2/2
Hamaya (5) Schifferli (14) Griffel (12)
-
-
1/1 1/1
1/1 1/1 1/1 1/1 1/1 1/1 46/53 (87%)
1/1 0/1 0/1 111 0/1 1/I 15/53 (28%)
0/1 1/I 1/1 0/1 0/1 1/1 26/53 (49%)
0/1
-
0/1 1 /I NA NA NA NA 9/15 (60%)
0/1 NA NA 1 /1 NA 1/I -___ 30/34 (88%)
Kobayashi (7) CadnaoaDhornchai (151 . . . , Present case Total
-
1/1
-
-
-
-
-
-
-
8/55 (15%)
7/55 (13%)
1/1 1/1 40/55 (73%)
1/1
1 /1 1/1 1/1 NA 111 41/45 (91%)
NA, not available; US, ultrastructure; RA, random arrangement; OA, orderly arrangement; pd, periodicity; MT, microtubular; MF, microfibrillary ; GF, granulated filament ; LS, lamellar structure. -, all negative.
919
Acta Pathologica Japonica 40 (12) : 1990 Findings paraprot.
~~~~~
0111 NA 017 NA NA 011 012 012 NA 011 NA 011 011 011 0127
(0%)
NA
-
+
NA
NA NA
NA
-
+ +
9/35 (26%)
ANA
319 0112 318 017 214 313
212 NA
011 011 NA 011 011 011 13/50 (26%)
yik
C3 NL/L
Clq/C4 NL/L
+/-
PRI
references
NA 015 NA NA NA NA NA NA NA 011 NA NA 011 111 118 (13%)
1110 1210 NA NA
1110 1111 NA NA 311 NA 1I 0 210 NA 1I 0 1I 0 1I 0 1I 0 1I 0 2/35 (6%)
615 2110 414 512 113 211 1I 1 012 1I 0 1I 0 o/ 1 1I 0 1I 0 1I 0 26/55 (47%)
CLL 1/11, MCTD 1/11
310 4/0 1I 0
2/o 1I 0 011 1I 0 1I 0 1I 0 011 2/39 (5%)
nant lymphoma ; LCD, light-chain disease; ATA, antithyroglobulin crosornal antibody ; BMG, benign monoclonal gammopathy. positive in serum imrnunoelectrophoresis ; -, negative.
LCD 717
0s 114, FG 414 RA 113 M L 112 T B 111
ATA 111, AMA 111 BMG 111 BMG 111
antibody; AMA,
antirni
+,
deposits comprised arrays of cisternal, serpiginously curvilinear, lamellar structures measuring 25 nm in width that were arranged in parallel with a periodicity of 5 0 nm (Fig. 5). The peripheral capillaries were almost obliterated in areas of marked neutrophilic and macrophagic infiltration. The macrophages had numerous enlarged lysosomes showing no microlamellar structure (Fig. 3). The mesangial cells were moderately proliferated without any particular abnormality (Fig. 4). The foot processes of the epithelial cells showed diffuse effacement. There
Finding j lambda
Us
6/6 9/9
3,'6 8/9
5/5 7/7 NA 1/2 1/1
5/5 117 NA 1/2 0/1
MT MF MT MF MF GF MF MF
NA
NA
MF
kappa ~-
0/1 0/1 NA NA NA NA 1/1 1/1 1/ I 0/1 1/I 0/1 ____ 30/34 24/34 (88%) (71%) ____-
MT MF MT MF MT ML
width/pd (nm) 27/27 11-30 20-35 20 10-19.5 12 7.5-10 10 25/10 8-12 18-22 10/25 >9 20/20 15-20 10-20 25/50
RA/OA OA RA 9/12 OA 3/12 RA RA RA RA RA OA RA OA OA OA RA OA OA
were neither organized deposits nor amorphous dense deposits on the tubular basement membrane. The second renal biopsy was performed at the Jichi Medical School Hospital two years after the initial hospitalization. The kidney tissue included 10 glomeruli. There were 2 glomeruli with adhesion and one with a small cellular crescent. All 10 glomeruli were slightly enlarged, but the glomerular size was reduced in comparison with the first biopsy (230+15 p m in diameter). The glomeruli still showed lobular accentuation due to mesangial hypercellularity, although nodular sclerotic lesions had become less apparent. Tubular atrophy and interstitial fibrosis with focal lymphocytic infiltration were seen ( 2 5 3 0 % of the total field).
DISCUSSION We have reported a patient who had a rare combination of lobular glomerulonephritis with microlamellar organized deposits, benign monoclonal IgG lambda paraproteinemia, and the appearance of anti-DNA antibody. The patient exhibited all the typical features of the newly described g lo merulo pat hy, immu nota ctoid g lomerulopathy (1). First, the clinical triad of severe hypertension, proteinuria and microscopic hematuria was followed by declining renal function over a period of 3 years. Second, histological studies showed mesa ngia I expansion and prominent deposition of extracellular crystalline structures in the mesangial matrix and capillary loops, which appeared not to be amyloid but rather composed of various immunoglobulins and complement. Third, the possibility of underlying SLE was ruled out by repeated
920
Organized Dense Deposits (Joh et a/.)
serological examinations. Unusually, our patient showed benign monoclonal gammopathy (IgG lambda paraproteinemia), whereas Korbet et a/. (1) were unable to find any paraproteinemia in either 9 patients examined by serum protein electrophoresis or 5 patients who underwent urinary immunoelectrophoresis. Anti-DNA antibody, which was not examined by Korbet et a/., was positive in our patient. Prominent neutrophilic infiltration of the glomeruli with swollen endothelial cells was associated with hypocomplementemia in our patient, whereas neither a cellular inflammatory reaction nor a decrease in the serum complement level was reported by Korbet et a/. in 11 patients. Electron-dense deposits showed a microlamellar structure in the present case, whereas a microtubular structure was seen by Korbet et a/. These discrepancies prompted us t o review previous similar reports. We found 5 5 cases in the literature which showed ultrastructural evidence of organized crystalline structures which were not caused by amyloidosis, SLE, cryoglobulinemia (except for one of 3 cases reported by Sturgill et a/. (4)) or multiple myeloma (Tables 1 and 2) (1-15). The patients comprised 18 females and 3 7 males with an age range of 10-80 years. Proteinuria was a common feature in all 5 5 patients. In 3 3 of them (60%), proteiuria reached the nephrotic level (3.0 g/ day). Microhematuria was seen in 3 9 out of 44 patients (89%), and hypertension was found in 31 out of 5 5 patients (56%). Decreased levels of C, and C,,/C, were seen in 2 out of 3 9 patients (5%) and in 2 out of 3 5 patients (6%), respectively. Renal dysfunction with a creatinine clearance of less than 7 0 ml/min was seen in 26 of the 55 cases (47%). None of 2 7 cases studied had Bence-Jones proteinuria. Paraprotein was found in 9 out of 3 5 patients, 7 of whom had light-chain disease (IgG kappa type) (6) whereas the patient reported by Cadnapaphornchai and Sillix (15) and the present patient had IgG lambda paraproteinemia. Antinuclear antibody was positive in 13 out of 50 cases (26%), but anti-DNA antibody was found only in the present case. One of 5 3 patients studied (2%) exhibited cryoglobulinemia. Six patients had underlying diseases including chronic lymphocytic leukemia, mixed connective tissue disease, tuberculosis, otosclerosis, malignant lymphoma, hyperthyroidism, and benign monoclonal gammopathy. Characteristic morphological findings in the reported cases are shown in Table 2. No morphological descrip tions based on light microscopy were explicitly mentioned in some reports. Mesangial hypercellularity and nodular formation appeared to be proportional to the severity of the disease process. The degree of involvement of the glomerular capillary wall seemed to vary in each case from a pattern resembling membranoprolifer-
ative glomerulonephritis (MPGN) to one resembling membranous glomerulonephritis (MGN). In the cases which resembled diffuse mesangioproliferati\e, glomerulonephritis (DPGN), the deposits in the gliomerular basement membrane were rather inconspicuous by light microscopy. Light microscopy demonstrate0 DPGN in 8 cases (15%), MGN in 7 cases (13%) and MPGN in 40 cases (73%). The cases showing a MPGNi pattern rarely had acute lesions or hypocomplementemia. There were only 6 MPGN cases: the present one, the case reported by Cadnapaphornchai and Sillix (15), the case reported by Hamaya and Doi (5), and 3 cases described by Mazzucco et a/. (2), in which acute lesions with leukocytic infiltration and endothelial swelling were present. lmmunofluorescence studies showed that thle lesions contained various immunoglobulin isotypes, complement and light chains. Components of IgG, Cs, C,, and kappa light chain were frequently positive in 46 out of 5 3 cases (87%), 41 out of 4 5 cases (91%), 3 0 out of 3 4 cases (88%) and 30 out of 3 4 cases (8893, respectively. IgM and lambda light chain were positive in 2 6 3ut of 5 3 cases (49%) and in 2 4 out of 34 cases (71%). IgA was positive in 15 out of 5 3 cases (28%). Except for the 6 out of 7 cases of light-chain disease (5) and the 2 cases of benign monoclonal gammopathy (15), kappa and lambda light chains were both positive. Electron microscopy revealed crystalloid structures 10-35 nm wide in the mesangium and glomerular capillary loops. These crystalline structures were sometimes microtubular or microlamellar, and sometimes microfibrillar or in the form of granulated filaments. The former group had electron-lucent central cores in crosssection, and most of the microtubular structures (except those in Schifferi’s case) exhibited orderly deposition of parallel microtubule arrays with a certain periodicity. The microtubules were of various widths : 3 5 rim, 27 nm, 25 nm, 2 0 nm and 10 nm. The latter showed a crisscross arrangement or contained randomly arranged nont ubula r and branching microfibrilla ry st ruct uri:s. These structures had thinner components than the first group, measuring 3 0 nm, 2 0 nm, 18 nm, 1 5 nm, 1 2 nm, 11 nm and 10 nm. All these crystalline structures h,ad microfibrils more than 9 nm wide, and thus could be differentiated from amyloidosis, in which thick-walled microfibrils measuring 9 nm in diameter are seen. Although the deposits were immunologically and morphologically similar to some deposits reported in cryoglobulinemia (161, the serum of the reported patients contained no cryoglobulin. The microtubular or microfibrillary structures reported differed from the lesions of cryoglobulinemia, which de onstrate paired annuilar structures or curved cylinders separated by an electron-lucent space (16). The presence of extracellular fibrilllary mate-
P
Acta Pathologica Japoriica 40 (12) : 1990
rials has been observed in a wide variety of glomerulopathies (17). Most often these materials represented collagen, fibrin, o r commonly observed components of the glomerula r basement membrane o r mesa ngia I matrix. However, immunofluorescence studies indicate a different origin f o r the fibrillary material in this condition. No plausible mechanism for the genesis of these specific microfibrils has yet been proved. Korbet et a/. (1) speculated that the glomerular deposition of fibrils could be related t o a high concentration of plasma proteins in the glomeruli, but it is unclear what physicochemical mechanism would induce these so-called i m munotactoids t o form. Schifferli et a/. (14) suggested that the disease might be related to the deposition of circulating insoluble immune complexes in both skin and glomeruli, followed by their crystallization. Cadnapaphornchai and Sillix (15) also documented the recurrence of organized dense deposits in the renal allograft i n the patient with IgG lambda monoclonal gammopathy. When the deposits are composed of uniform subcomponents having strong intermolecular attraction, it is possible that abnormal production of monoclonal immunoglobulins, like that seen in the present case, would help t o induce these lesions.
REFERENCES Korbet SM, Schwartz MM, Rosenberg BF, et a/. Immunota cto id g lo merulo pat hy. Medicine (Ba Itimo re) 60 : 228-243, 1985. h4azzucco G, Casanova S, Donini U, et a/. Glomerulonephritis with organized deposits : A new clinicopathological entity ? Light-, electron-microscopic and immunofluorescence study of 12 cases. Am J Nephrol 10: 21-30, 1990. Eurgin M, Hofmann E, Reutter FW, e t a/. Familial glomerulopathy with giant fibrillar deposits. Virchows Arch [A] 388: 313-326, 1980. S,turgill BC, BoIton WK, and Griffith KM. Congo red-
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negative amyloidosis-like glomerulopathy. Hum Pathol 1 6 : 220-224, 1985. Hamaya K and Doi K. Fingerprint-like straight crystalloid microfilaments in lobular glomerulonephritis. Acta Pathol Jpn 3 5 : 767-773, 1985. Alpers CE, Rennke HG, Hopper J Jr, and Biava CG. Fibrillary glomerulonephritis : An entity with unusual immunofluorescence features. Kidney Int 3 1 : 781 789, 1987. Kobayashi Y, Fujii K, Kurokawa A, et a/. Glomerulopathy with amyloid-stain-negative microfibrillar glomerular deposits. Nephron 48 : 33-39, 1988. Rosenmann E. Brisson ML, Bercovitch DD, and Rosenberg A. Atypical membranous glomerulonephritis with fibrillar subepithelial deposits in a patient with malignant lymphoma. Nephron 48: 226-230, 1988. Rosenmann E and Eliakim M. Nephrotic syndrome associated amyloid-like glomerular deposits. Nephron 18: 301-308, 1977. Olesnicky L, Doty SB, Bartani T, and Pirani CL. Tubular microfibrils in the glomeruli of membranous nephropathy. Arch Pathol Lab Med 108: 902-905, 1984. Schwartz MM and Lewis EJ. The quarterly case: Nephrotic syndrome in a middle-aged man. Ultrastruct Pathol 1 : 575-582, 1980. Griffel B and Bernheim J. Glomerular deposits in idiopathic membranous glomerulopathy. Arch Pathol Lab Med 1 0 4 : 56-57, 1980. Duffy JL, Khurana E, Susin M, et a/. Fibrillary renal deposits and nephritis. Am J Pathol 1 1 3 : 279-290, 1983. Schifferli JA, Merot Y, Cruchaud A, and Chatelanat F. lmmunotactoid glomerulopathy with leukocytoclastic skin vasculitis and hypocomplementemia : A case report. Clin Nephrol 2 7 : 151-155, 1987. Cadnapaphornchai P and Sillix D. Recurrence of monoclonal gammopathy-related glomerulonephritis in renal allograft. Clin Nephrol 31 : 156-159, 1989. Feiner H and Gallo G. Ultrastructure in glomerulonephritis associated with cryoglobulinemia. A report of six cases and review of the literature. Am J Pathot 88: 145-162, 1977. Duffy JL and Churg J. Extracellular fibrils in the renal glomerulus. Ultrastruct Pathol 6 : iii-vi, 1984.
