REVIEW
Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis Clinical Features, Immunopathology, and Molecular Analysis Joel N . Buxbaum, M D ; Joseph V. Chuba, P h D ; Gerard C. Hellman, M D ; Alan Solomon, M D ; and Gloria R. Gallo, M D
Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.
JVlonoclonal immunoglobulin deposition disease, as defined by monotypic light or heavy chain deposits in tissue, may be fibrillar, as in light chain amyloid, or nonfibrillar, as in light chain or light and heavy chain deposition diseases. Either form may occur in overt multiple myeloma, but many patients with this disease have no evidence of neoplastic plasma cell proliferative disease. Light chain deposition disease of the kidney was first reported in 1973 ( 1 ) ; the systemic nature of the deposition, in 1976; and the probability that heavy as well as light chain deposition could occur, in 1980 (2, 3 ) . More than 150 well-documented cases of the syndrome have now been reported from various institutions in many countries (4-55). Based on the clinical and pathologic findings in 13 patients with light chain or light and heavy chain deposition seen at or referred for analysis to our institution between 1970 and 1987, the results of immunoglobulin biosynthesis experiments, and our review of the literature, we compare the features and pathogenesis of the fibrillar (amyloidotic) and nonfibrillar forms of the disease, both of which frequently present with clinical evidence of nephropathy. Although significant proteinuria indicates the presence of renal dysfunction, the combination of albuminuria and hypogammaglobulinemia specifically suggests a monoclonal plasmacytic disorder. Similarly, neuropathy or cardiomyopathy in the presence of low serum immunoglobulins suggests this class of diseases. Monoclonal serum or urine proteins will be detected in 8 0 % of patients with such a disorder and marrow plasmacytosis with evidence of restricted clonality in an even larger proportion. Appropriate immunopathologic analysis of affected tissue will provide the diagnosis.
Materials and Methods
Annals of Internal Medicine. 1990;112:455-464. From New York University School of Medicine, New York V.A. Medical Center, and Lenox Hill Hospital, New York, New York; and University of Tennessee, Knoxville, Tennessee. For current author addresses, see end of text.
We included patients with evidence of plasmacytic dyscrasias whose tissues, obtained by biopsy or at autopsy, contained nonCongophilic, monoclonal light chain tissue deposits identified by immunofluorescence or immunoperoxidase staining with monospecific antiheavy and light chain antisera (55). Patients K3 and L2, who had multiple myeloma, were identified retrospectively by characteristic ultrastructural findings. Most of the patients were seen at the New York University Medical Center. For Patients K4 and K5, only pathologic material was reviewed. Serum and urinary immunoglobulins were identified by a microimmunoelectrophoretic procedure adapted to thin layer agarose gel plates
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
455
(56). Immunohistologic studies in each patient included staining with antibodies specific for immunoglobulin heavy (gamma, alpha, and mu) chains, immunoglobulin light (kappa and lambda) chains, fibrin, C3, Clq, and in some cases amyloid P component. Electron microscopy of tissues was done conventionally (55). Radiolabeling and analyses of immunoglobulins synthesized by bone marrow cells were done as previously described (57). Some information about Patients K4, K5, K7, and K8 has been previously reported (41, 48, 55). However, new data on their clinical features and the results of immunoglobulin biosynthetic analysis are now presented. Clinical information was obtained from clinical records provided by referring physicians when patients were not seen in our own institutions. Results Clinical Features Our series included 9 men and 4 women; when symptoms began, their ages ranged from 35 to 71 years. Clinical features are shown in Tables 1 and 2. All patients had significant renal disease; in 11, it was the major manifestation. Patient K6 initially presented with gastrointestinal bleeding related to coexisting amyloid infiltration of the stomach, and the azotemia appeared to be secondary to renal hypoperfusion rather than deposition of monoclonal immunoglobulin in the kidneys. Although patient K8's initial symptoms were related to mild azotemia, his major clinical problem was cardiac in nature. Eleven of the thirteen had serum creatinine levels over 124 u,mol/L at diagnosis. Six had acute or severe renal failure as the initial manifestation; in the remainder, azotemia developed more gradually. Primary tubular disorders could not be evaluated because of coexisting renal insufficiency. Eleven patients had proteinuria levels of over 0.3 g / d. Three of five patients whose daily urine contained more than 3 g of protein exhibited the complete nephrotic syndrome with hypoalbuminemia (under 30 g / L ) and hypercholesterolemia (over 9 m m o l / L ) . In contrast, Patient K8, even late in his course, had 170
mg of free monoclonal kappa light chain as the only protein in a 24-hour urine specimen and was the only patient in whom the monoclonal light chain was the major urinary protein. Where quantified (Patients K2, K4, K5, K7, LI, A K 1 , GL1, and GL2), free L-chains represented from 0% to 15% of total urinary protein. Occasional patients had microscopic hematuria, but none had erythrocyte casts. Hypertension, recorded in the clinical record as a systolic blood pressure over 150 mm Hg or a diastolic pressure over 90 mm Hg, was common; however, in most cases, whether the increase in blood pressure preceded the occurrence of the deposition disease was difficult to discern. Hypertension was usually not severe and was controlled in different patients by various antihypertensive medications. In all but one of the cases identified premortem (Patient K 8 ) , renal disease dominated the clinical presentation and diagnosis was made by renal biopsy. Four patients were treated with chronic hemodialysis, three ultimately receiving cadaveric renal transplants. Patient K8's clinical manifestations were primarily cardiac: atrial fibrillation and refractory congestive heart failure. Cardiac catheterization showed increased right-sided filling pressures, suggesting a noncompliant myocardium and reduced cardiac output. Extensive kappa light chain deposition was shown by both endomyocardial and renal biopsy. Three patients were studied with echocardiography because of cardiac symptoms. Patient K5 had an unremarkable study; Patient K6 had concentric left ventricular and left atrial enlargement; and Patient K l had thickening of the interventricular septum and borderline posterior ventricular wall thickening. Patient LI had angina pectoris and congestive heart failure with a left bundle branch block on electrocardiogram. Patient GL2 had roentgenographic evidence of cardiomegaly with a normal electrocardiogram. In the patients who were autopsied, complete analysis for nonamyloidotic light
Table 1. ILu'tial Clinical Fea,tures of Patients w.ith Light Chain and jLight and Heavy CI tain Deposition Patient
Blood Pressure
Serum Creatinine
mm Hg
/zmol/L
Kl K2 K3
120/80 220/110 130/70
2033 1061 1061
Yes Yes Yes
K4 K5 K6 K7 K8
170/90 200/100 140/80 165/100 140/90
937 884 159 230 221
Yes Yes No No No
LI L2
200/100 120/70
80 636
No Yes
AK1
200/110
212
GL1 GL2
190/100 160/100
159 124
No
Acute Renal Failure
Disea.ses
Proteinuria
Proteinuria, Light Chain*
g/d
%
Nephrotic Syndromef
NAJ 10 NA
No No No
0 Trace NA 0 100
No No No No No
6.3 3.3
4 NA
Yes No
No
8.9
1
Yes
No
1.6-^ 6.4
15 5
No Yes
2-3 2 Over 0.6 2.3 0.5-0.8 0.3 3 to 11 0.17
* Approxirnated from densitometry of urine electroph oresis. t Urine pnDtein over 3 g/d; senlm albumin less than 210 g/L; serum cholesterol more than 9 mmol/L. % N A = nt available.
456
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
Table 2. Clinicopathologic Plasmaa ytic Dyscrasias Patient Plasma Cells, %
Fimatures of Patients
with Light Chair ? and Light and He,avy Chain Deposition
Bone Marrow Kappa to Lambda Myeloma Chain Ratio
Hypercalcemia
Kl
Packed
100:1
Yes
No
K2
Packed
ND*
Yes
Yes
K3
20
ND
Yes
No
K4 K5 K6
10-15 12 Increased
ND 50:1 ND
Possible Possible No
Yes Yes No
K7
2
ND
No
No
K8
19
ND
Possible
Yes
LI L2
Normal 30
ND ND
No Yes
No No
5-10 Increased 11
30:1 ND 1:30
No No No
No No No
AK1 GL1 GL2
Dist *ases Related
Clinical Features
Renal failure, infection Renal failure, myeloma Renal failure, cardiac arrest Chronic hemodialysis Renal transplant Gastric hemorrhage from amyloidosis Renal transplant, sepsis Chronic congestive heart failure Unrelated death Amyloidosis with renal vein thrombosis Renal transplant Renal cell carcinoma Nephrotic syndrome, cardiomegaly
to
Survival from Onset of Symptoms 5 mo 3 mo 1 mo
>2yt >5yt 5 mo 10 y 24 mo 10 mo 2 mo
>6yt 9y
>4y|
*ND =: not done. t Still living.
chain deposition was not available, although the two patients with concomitant amyloidosis had Congo Red binding deposits in the myocardium, the coronary vessels, or both. Therefore, although several patients had clinically detectable cardiac disease, light chain deposits were documented by tissue analysis in the heart of only Patient K8. The findings in the others could have resulted from different types of cardiac pathology. Nine of twelve patients were hypogammaglobulinemic according to serum protein electrophoresis, Immunoelectrophoresis, or quantitative determination of the individual immunoglobulin classes by radial immunodiffusion (Table 3). Two of the remaining patients (Patients K4 and L I ) had low normal values. Seven of twelve had monoclonal serum immunoglobulins: one had IgG kappa; two, IgG lambda; one, IgA kappa; two, free kappa; and one, free lambda L-chains. Seven patients had free light chains in the urine; three had lambda and four, kappa. In two of the patients with the nephrotic syndrome, Patients AK1 and GL2, the monoclonal proteins found in the serum were also in the urine. In most cases, the amounts were small. In Patients K4 and K7, no monoclonal proteins were found in either the serum or the urine, even after concentrating the urine up to 400-fold. Light microscopic examination of bone marrow obtained by aspiration, biopsy, or both, usually showed more than 5% plasma cells (Table 2). In Patient LI, the marrow was judged to be totally normal. In Patient K7, only 2% plasma cells could be identified. In the others, the plasma cell number was increased from 5% to 100%. In four patients whose bone marrow smears were examined with immunofluorescence (Patients K l , K5, AK1, and GL2), the kappa to lambda
ratios were altered, with the increase corresponding to the type of light chain deposited in the tissues. Multiple myeloma was diagnosed unequivocally in Patients K l , K2, K3, and L2. It was suspected in three others (Patients K4, K5, and K8) with hypercalcemia, although these patients did not have lytic lesions or other manifestations of neoplastic behavior. Five patients died shortly (1 to 6 months) after becoming ill, including the four with clinically diagnosed multiple myeloma. Three of these four deaths were related to acute renal failure. In the fourth, a fatal arrhythmia supervened. Patient K6 died after surgery for gastrointestinal bleeding related to amyloid infiltration of the stomach. Patient K8 died from intractable heart failure produced by the deposition of monoclonal kappa chains in his myocardium 2 years after his initial presentation. Patient GL1 died from chronic renal failure 8 years after diagnosis. In the interim, he had a right total nephrectomy for a renal cell carcinoma. The glomerular histologic abnormalities found in the nonmalignant portion of the removed kidney were similar to those previously seen on renal biopsy. Patient LI died from an unrelated illness. Eight patients received some form of chemotherapy. One, Patient K2, died from myeloma within 3 months of the onset of disease. Patient K8 received only prednisone (40 to 80 mg daily) with no apparent response. Patient K4 received four courses of melphalan, 8 mg per day for 4 days, and prednisone, 75 mg per day for 7 days, before receiving chronic hemodialysis. Patient K5 received similar monthly therapy while on dialysis. After 3 months, monoclonal kappa chains could no longer be detected in his urine, and treatment was stopped. One year later, he received a cadaver kidney. Patient K7 received three monthly courses of melpha-
15 March 1990 • Annals ofInternal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
457
Table 3. Imn:mnoglobulins in Light Chain and Light and Heavy Chain Deposition Dise< ases Patient
Serum Polyclonal
Biosynthetic Products
Urine Monoclonal
Kl K2
Low Low
IgG kappa Free kappa
Kappa Kappa
K3 K4 K5
Low Normal Low
Free kappa None None
K6 K7
ND Low
ND None
ND None Trace Kappa ND None
K8
Low
None
Kappa
LI L2 AK1
Normal Normal Low
None Free lambda IgA kappa
Lambda Lambda IgA kappa
GL1
Low
IgG lambda
Lambda
GL2
Low
IgG lambda
IgG lambda
ND* Kappa dimer, monomer, fragments ND Kappa monomer Kappa dimer, monomer, fragment ND Kappa dimer, monomer, fragment Kappa dimer, monomer, fragment ND ND Alpha fragment and multimers, free kappa G a m m a fragment, intact lambda and lambda fragments, polymers ND
* N D = not clone.
Ian and prednisone. During the third course, he had profound thrombocytopenia requiring platelet transfusions, and he refused further chemotherapy. His serum and urine contained no monoclonal protein at diagnosis. However, bone marrow analysis, which had shown monoclonal kappa production before therapy, indicated a marked reduction after the three treatment cycles. The same results were obtained in several studies done while he was on hemodialysis and after transplantation. However, 3 years after transplantation and 10 years after diagnosis, the amount of free kappa production increased, despite the continued administration of immunosuppressive agents. He subsequently died from systemic sepsis acquired during hospitalization for surgical treatment of peripheral arterial insufTable 4. Risnal Pathology in Light Chain and Light and Patient Glomeruli
ficiency, apparently unrelated to his primary disease. Patient AK1 received three different chemotherapeutic regimens. Initially, he received daily melphalan and prednisone with little response. He was subsequently given a 4-month course of carmustine, doxorubicin, vincristine, and prednisone with subjective but little objective improvement. He was then switched to cyclophosphamide (50 to 100 mg per day) and prednisone (10 mg per day) for a 7-month period. His abnormal serum and urine proteins gradually disappeared. His bone marrow analyses showed diminishing amounts of free light chains and alpha fragment and an increase in normal polyclonal immunoglobulin production which was reflected in quantitative normalization of his serum globulins. Patient GL2, whose
Heavy Chain Deposition 1Diseases
Light Microscopy Bence-Jones Casts
Amyloid
Immunofluorescence Glomerular Tubular Basement Basement Membrane Membrane
Kl K2 K3 K4 K5 K6
Normal Normal Normal Mesangial nodules Increased mesangium Normal
Yes Yes Yes Yes Yes No
No No No No No Yes
Kappa Kappa NDf Kappa Kappa Kappa
Kappa Kappa ND Kappa Kappa Kappa
K7
Mesangial nodules Sclerosis
No No No Yes
No No No Yes
Kappa
Kappa Kappa
ND
ND
No
No
Alpha, kappa
Focal
No No
No No
G a m m a , lambda G a m m a , lambda
Focal
K8J LI L2
AK1 GL1 GL2
Normal Increased mesangium, confluent deposits Mesangial nodules Confluent deposits
-
* G = graiHilar; F = fibrillar; C = conflueint. t N D = nc)t done. X See refere:nce 48.
458
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
diagnosis was established during investigation of asymptomatic proteinuria discovered during a routine physical examination, was treated with melphalan and prednisone (as above) for 1 year with reduction of her proteinuria to 0.6 g/d. At present, 4 of the 11 patients diagnosed clinically (Patients K4, K5, A K 1 , GL2) are living, up to 6 years from the time of diagnosis. Patients K5, K7, and AK1 received cadaveric renal transplants after periods of hemodialysis. Each was treated with chemotherapy before transplantation. In Patients K5 and A K 1 , the monoclonal protein disappeared from the serum and urine before transplantation; this disappearance was confirmed by repeat biosynthetic analysis in Patient AK1. Immunopathology Table 4 summarizes the pathologic findings in the 13 patients whose renal disease was classified as light chain or light and heavy chain deposition disease. Of the 11 renal biopsies examined with immunofluorescence, 10 had monoclonal immunoglobulin deposits that did not bind Congo Red. In 2 of the 13 patients, the diagnosis of light chain deposition disease was made retrospectively by electron microscopy of autopsy specimens that showed the distinctive clustered punctate deposits in glomerular and tubular basement membranes in the presence of multiple myeloma. One of these patients had free kappa chains in the serum, and the other had lambda light chains in both the serum and urine. Among the 11 patients examined by immunofluorescence, four different types of monoclonal deposits were found: 7 patients had kappa light chains; 1, lambda light chains; 1, alpha and kappa chains; and 2, both gamma and lambda chains. Hence, among our patients, the ratio of kappa to lambda producers was 9/4. Patients K6 and L2, in addition to
having the nonamyloid light chain deposition, had focal deposits of Congo Red binding material in renal blood vessels and myocardium. Patient K6 also had significant infiltration of the gastric wall with amyloid.
Biosynthetic Analysis Analyses of the immunoglobulins synthesized by aspirated bone marrow cells in short-term tissue culture were completed in seven of the patients (Table 3). All the patients synthesized immunoglobulin-related polypeptides corresponding to the class of molecule found in the tissue deposits. In two patients whose serum and urine contained no M-protein, the proteins synthesized by the cultured bone marrow cells were the only evidence of monoclonal immunoglobulin synthesis. Bone marrow cells from all but one patient contained, in addition to intact light chains (determined by their antigenicity and molecular mass), labeled polypeptides bearing light chain antigenic determinants that were shorter than expected for normal chains. Detailed analysis of the production of one such fragment, which represented a major cytoplasmic molecule, suggested a synthetic, not degradative, origin. In some cases, more than one such fragment could be identified. In Patients GL1 and A K l , whose deposits were stained with both antiheavy and antilight chain sera, the plasma cells produced labeled proteins that were precipitable with antibodies specific for the deposited heavy and light chain determinants. However, the molecular sizes of the labeled antigamma precipitable molecules in Patient GL1 and the anti-alpha precipitable species in Patient A K l indicated that the major intra- and extracellular immunoglobulins were covalently and noncovalently linked polymers of heavy chain fragments and light chains. The truncated heavy
Table 4. ,(Continued) Immunofluorescence Blood Vessels
Kappa Kappa ND Kappa Kappa Kappa
Amyloid P Component
-
Absent Absent ND ND ND ( + ) Amyloid, ( — )nonamyloid Absent ND Absent ( + )Amyloid, ( —)nonamyloid Absent
_ -
Absent Absent
Kappa
-
Lambda ND
Glomerular Basement Membrane and Mesangium
_
Electron Microscopy* Tubular Basement Membrane
G G G G
G G G G G
—
—
G
G G
-
Blood Vessels
-
_ G G G G F G
-
G
G
F
C
-
-
Minimal C
_ -
_ -
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
459
chains also appeared to be synthetic, not proteolytic, products. Discussion Diagnosis of light chain deposition disease is made on the basis of the immunohistologic findings obtained when affected tissues from biopsy or autopsy are examined with reagents of demonstrable sensitivity and specificity. The deposits are nonCongophilic. Diffuse linear staining of glomerular and tubular basement membranes and vessels is seen only with antibody directed against a single class of immunoglobulin light chain. Kidney tissues from patients with light and heavy chain deposition disease, in addition to having glomerular staining for only one type of light chain, react strongly with antisera directed against the constant region determinants of a single heavy chain class. The tubular basement membranes and vessels are stained less uniformly, with focal rather than diffuse involvement. In contrast to immune complex diseases which have granular deposits containing immunoglobulins of both light chain classes and C3, there is usually little or no staining with reagents specific for complement components. The most frequent form of nonamyloid monoclonal immunoglobulin deposition is kappa light chain deposition disease. Lambda light chain deposition represents 1 5 % to 2 0 % and combined light and heavy chain deposition, fewer than 10% of the reported cases. Table 5 compares the clinical features of our 13 patients with those in cases reported elsewhere. In addition, we have compared the clinical features of our patients with those in cases of light chain amyloidosis reported from the Mayo Clinic (57, 58). The dominant feature in our patients with light chain and light and heavy chain deposition disease, as well as in such patients from other centers, was significant renal disease. Ninety-two percent of our patients and 9 4 % of those from elsewhere had renal insufficiency at diagnosis. Similar percentages of patients had substantial nep h r o p a t h y proteinuria in addition to the excretion of monoclonal immunoglobulins. A few patients had one
or the other. The proportion of patients with light chain amyloid and proteinuria at diagnosis was similar to that found in light chain deposition disease, but the proportion with azotemia at presentation was somewhat lower in the amyloid group. Microscopic hematuria occurred in at least 20% of the reported cases. Since many of the cases studied were described by nephrologists or nephropathologists, the data on renal manifestations were quite complete and the incidence probably reliable. Fewer data were available on other clinical aspects of the disease. Hypogammaglobulinemia was more frequent in our patients than in those from elsewhere (Table 6). Fully 67% of the New York University group had low levels of most or all classes of serum immunoglobulins, a fraction slightly higher than the 56% reported from other centers. We believe that hypogammaglobulinemia in a patient with substantial albuminuria strongly suggests some form of monoclonal immunoglobulin deposition disease. The proportion of our patients with monoclonal serum proteins was similar to that reported elsewhere; however, other centers reported a slightly larger percentage of patients with urinary monoclonal light chains. Patients with light chain amyloid showed similar percentages of monoclonal serum and urine immunoglobulin components. In approximately 20% of cases, no monoclonal immunoglobulins were detected by conventional analysis. Our work in both light chain and light and heavy chain deposition and light chain amyloid shows that, when examined using sensitive radiolabeling techniques, cells from such patients produce monoclonal immunoglobulin polypeptides of the same class as those deposited in the tissues (57). We and others (12, 26, 55) have previously suggested that some patients who appear to have nonsecretory myeloma may have various forms of immunoglobulin deposition disease in which the absolute rate of monoclonal immunoglobulin synthesis is low and the protein products have high tissue affinity. The incidence of multiple myeloma in patients with deposition disease may be higher than in those with light chain amyloid. Our criteria for diagnosis of mye-
Table 5. Clink :aJ Features in Light CIlain and Light and Heavy C hain Chain Amyloiciosis Series
Hypertension
Proteinuria
Azotemia
Depositkm Diseases C Compared with Those of Light
Cardiac Features
Hepatic Features
Gastrointestinal Neurologic Features Features
n/N ()
Light chain an
Monoclonal Immunoglobulin Deposition Disease: Light Chain and Light and Heavy Chain Deposition Diseases and Their Relation to Light Chain Amyloidosis Clinical Features, Immunopathology, and Molecular Analysis Joel N . Buxbaum, M D ; Joseph V. Chuba, P h D ; Gerard C. Hellman, M D ; Alan Solomon, M D ; and Gloria R. Gallo, M D
Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.
JVlonoclonal immunoglobulin deposition disease, as defined by monotypic light or heavy chain deposits in tissue, may be fibrillar, as in light chain amyloid, or nonfibrillar, as in light chain or light and heavy chain deposition diseases. Either form may occur in overt multiple myeloma, but many patients with this disease have no evidence of neoplastic plasma cell proliferative disease. Light chain deposition disease of the kidney was first reported in 1973 ( 1 ) ; the systemic nature of the deposition, in 1976; and the probability that heavy as well as light chain deposition could occur, in 1980 (2, 3 ) . More than 150 well-documented cases of the syndrome have now been reported from various institutions in many countries (4-55). Based on the clinical and pathologic findings in 13 patients with light chain or light and heavy chain deposition seen at or referred for analysis to our institution between 1970 and 1987, the results of immunoglobulin biosynthesis experiments, and our review of the literature, we compare the features and pathogenesis of the fibrillar (amyloidotic) and nonfibrillar forms of the disease, both of which frequently present with clinical evidence of nephropathy. Although significant proteinuria indicates the presence of renal dysfunction, the combination of albuminuria and hypogammaglobulinemia specifically suggests a monoclonal plasmacytic disorder. Similarly, neuropathy or cardiomyopathy in the presence of low serum immunoglobulins suggests this class of diseases. Monoclonal serum or urine proteins will be detected in 8 0 % of patients with such a disorder and marrow plasmacytosis with evidence of restricted clonality in an even larger proportion. Appropriate immunopathologic analysis of affected tissue will provide the diagnosis.
Materials and Methods
Annals of Internal Medicine. 1990;112:455-464. From New York University School of Medicine, New York V.A. Medical Center, and Lenox Hill Hospital, New York, New York; and University of Tennessee, Knoxville, Tennessee. For current author addresses, see end of text.
We included patients with evidence of plasmacytic dyscrasias whose tissues, obtained by biopsy or at autopsy, contained nonCongophilic, monoclonal light chain tissue deposits identified by immunofluorescence or immunoperoxidase staining with monospecific antiheavy and light chain antisera (55). Patients K3 and L2, who had multiple myeloma, were identified retrospectively by characteristic ultrastructural findings. Most of the patients were seen at the New York University Medical Center. For Patients K4 and K5, only pathologic material was reviewed. Serum and urinary immunoglobulins were identified by a microimmunoelectrophoretic procedure adapted to thin layer agarose gel plates
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
455
(56). Immunohistologic studies in each patient included staining with antibodies specific for immunoglobulin heavy (gamma, alpha, and mu) chains, immunoglobulin light (kappa and lambda) chains, fibrin, C3, Clq, and in some cases amyloid P component. Electron microscopy of tissues was done conventionally (55). Radiolabeling and analyses of immunoglobulins synthesized by bone marrow cells were done as previously described (57). Some information about Patients K4, K5, K7, and K8 has been previously reported (41, 48, 55). However, new data on their clinical features and the results of immunoglobulin biosynthetic analysis are now presented. Clinical information was obtained from clinical records provided by referring physicians when patients were not seen in our own institutions. Results Clinical Features Our series included 9 men and 4 women; when symptoms began, their ages ranged from 35 to 71 years. Clinical features are shown in Tables 1 and 2. All patients had significant renal disease; in 11, it was the major manifestation. Patient K6 initially presented with gastrointestinal bleeding related to coexisting amyloid infiltration of the stomach, and the azotemia appeared to be secondary to renal hypoperfusion rather than deposition of monoclonal immunoglobulin in the kidneys. Although patient K8's initial symptoms were related to mild azotemia, his major clinical problem was cardiac in nature. Eleven of the thirteen had serum creatinine levels over 124 u,mol/L at diagnosis. Six had acute or severe renal failure as the initial manifestation; in the remainder, azotemia developed more gradually. Primary tubular disorders could not be evaluated because of coexisting renal insufficiency. Eleven patients had proteinuria levels of over 0.3 g / d. Three of five patients whose daily urine contained more than 3 g of protein exhibited the complete nephrotic syndrome with hypoalbuminemia (under 30 g / L ) and hypercholesterolemia (over 9 m m o l / L ) . In contrast, Patient K8, even late in his course, had 170
mg of free monoclonal kappa light chain as the only protein in a 24-hour urine specimen and was the only patient in whom the monoclonal light chain was the major urinary protein. Where quantified (Patients K2, K4, K5, K7, LI, A K 1 , GL1, and GL2), free L-chains represented from 0% to 15% of total urinary protein. Occasional patients had microscopic hematuria, but none had erythrocyte casts. Hypertension, recorded in the clinical record as a systolic blood pressure over 150 mm Hg or a diastolic pressure over 90 mm Hg, was common; however, in most cases, whether the increase in blood pressure preceded the occurrence of the deposition disease was difficult to discern. Hypertension was usually not severe and was controlled in different patients by various antihypertensive medications. In all but one of the cases identified premortem (Patient K 8 ) , renal disease dominated the clinical presentation and diagnosis was made by renal biopsy. Four patients were treated with chronic hemodialysis, three ultimately receiving cadaveric renal transplants. Patient K8's clinical manifestations were primarily cardiac: atrial fibrillation and refractory congestive heart failure. Cardiac catheterization showed increased right-sided filling pressures, suggesting a noncompliant myocardium and reduced cardiac output. Extensive kappa light chain deposition was shown by both endomyocardial and renal biopsy. Three patients were studied with echocardiography because of cardiac symptoms. Patient K5 had an unremarkable study; Patient K6 had concentric left ventricular and left atrial enlargement; and Patient K l had thickening of the interventricular septum and borderline posterior ventricular wall thickening. Patient LI had angina pectoris and congestive heart failure with a left bundle branch block on electrocardiogram. Patient GL2 had roentgenographic evidence of cardiomegaly with a normal electrocardiogram. In the patients who were autopsied, complete analysis for nonamyloidotic light
Table 1. ILu'tial Clinical Fea,tures of Patients w.ith Light Chain and jLight and Heavy CI tain Deposition Patient
Blood Pressure
Serum Creatinine
mm Hg
/zmol/L
Kl K2 K3
120/80 220/110 130/70
2033 1061 1061
Yes Yes Yes
K4 K5 K6 K7 K8
170/90 200/100 140/80 165/100 140/90
937 884 159 230 221
Yes Yes No No No
LI L2
200/100 120/70
80 636
No Yes
AK1
200/110
212
GL1 GL2
190/100 160/100
159 124
No
Acute Renal Failure
Disea.ses
Proteinuria
Proteinuria, Light Chain*
g/d
%
Nephrotic Syndromef
NAJ 10 NA
No No No
0 Trace NA 0 100
No No No No No
6.3 3.3
4 NA
Yes No
No
8.9
1
Yes
No
1.6-^ 6.4
15 5
No Yes
2-3 2 Over 0.6 2.3 0.5-0.8 0.3 3 to 11 0.17
* Approxirnated from densitometry of urine electroph oresis. t Urine pnDtein over 3 g/d; senlm albumin less than 210 g/L; serum cholesterol more than 9 mmol/L. % N A = nt available.
456
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
Table 2. Clinicopathologic Plasmaa ytic Dyscrasias Patient Plasma Cells, %
Fimatures of Patients
with Light Chair ? and Light and He,avy Chain Deposition
Bone Marrow Kappa to Lambda Myeloma Chain Ratio
Hypercalcemia
Kl
Packed
100:1
Yes
No
K2
Packed
ND*
Yes
Yes
K3
20
ND
Yes
No
K4 K5 K6
10-15 12 Increased
ND 50:1 ND
Possible Possible No
Yes Yes No
K7
2
ND
No
No
K8
19
ND
Possible
Yes
LI L2
Normal 30
ND ND
No Yes
No No
5-10 Increased 11
30:1 ND 1:30
No No No
No No No
AK1 GL1 GL2
Dist *ases Related
Clinical Features
Renal failure, infection Renal failure, myeloma Renal failure, cardiac arrest Chronic hemodialysis Renal transplant Gastric hemorrhage from amyloidosis Renal transplant, sepsis Chronic congestive heart failure Unrelated death Amyloidosis with renal vein thrombosis Renal transplant Renal cell carcinoma Nephrotic syndrome, cardiomegaly
to
Survival from Onset of Symptoms 5 mo 3 mo 1 mo
>2yt >5yt 5 mo 10 y 24 mo 10 mo 2 mo
>6yt 9y
>4y|
*ND =: not done. t Still living.
chain deposition was not available, although the two patients with concomitant amyloidosis had Congo Red binding deposits in the myocardium, the coronary vessels, or both. Therefore, although several patients had clinically detectable cardiac disease, light chain deposits were documented by tissue analysis in the heart of only Patient K8. The findings in the others could have resulted from different types of cardiac pathology. Nine of twelve patients were hypogammaglobulinemic according to serum protein electrophoresis, Immunoelectrophoresis, or quantitative determination of the individual immunoglobulin classes by radial immunodiffusion (Table 3). Two of the remaining patients (Patients K4 and L I ) had low normal values. Seven of twelve had monoclonal serum immunoglobulins: one had IgG kappa; two, IgG lambda; one, IgA kappa; two, free kappa; and one, free lambda L-chains. Seven patients had free light chains in the urine; three had lambda and four, kappa. In two of the patients with the nephrotic syndrome, Patients AK1 and GL2, the monoclonal proteins found in the serum were also in the urine. In most cases, the amounts were small. In Patients K4 and K7, no monoclonal proteins were found in either the serum or the urine, even after concentrating the urine up to 400-fold. Light microscopic examination of bone marrow obtained by aspiration, biopsy, or both, usually showed more than 5% plasma cells (Table 2). In Patient LI, the marrow was judged to be totally normal. In Patient K7, only 2% plasma cells could be identified. In the others, the plasma cell number was increased from 5% to 100%. In four patients whose bone marrow smears were examined with immunofluorescence (Patients K l , K5, AK1, and GL2), the kappa to lambda
ratios were altered, with the increase corresponding to the type of light chain deposited in the tissues. Multiple myeloma was diagnosed unequivocally in Patients K l , K2, K3, and L2. It was suspected in three others (Patients K4, K5, and K8) with hypercalcemia, although these patients did not have lytic lesions or other manifestations of neoplastic behavior. Five patients died shortly (1 to 6 months) after becoming ill, including the four with clinically diagnosed multiple myeloma. Three of these four deaths were related to acute renal failure. In the fourth, a fatal arrhythmia supervened. Patient K6 died after surgery for gastrointestinal bleeding related to amyloid infiltration of the stomach. Patient K8 died from intractable heart failure produced by the deposition of monoclonal kappa chains in his myocardium 2 years after his initial presentation. Patient GL1 died from chronic renal failure 8 years after diagnosis. In the interim, he had a right total nephrectomy for a renal cell carcinoma. The glomerular histologic abnormalities found in the nonmalignant portion of the removed kidney were similar to those previously seen on renal biopsy. Patient LI died from an unrelated illness. Eight patients received some form of chemotherapy. One, Patient K2, died from myeloma within 3 months of the onset of disease. Patient K8 received only prednisone (40 to 80 mg daily) with no apparent response. Patient K4 received four courses of melphalan, 8 mg per day for 4 days, and prednisone, 75 mg per day for 7 days, before receiving chronic hemodialysis. Patient K5 received similar monthly therapy while on dialysis. After 3 months, monoclonal kappa chains could no longer be detected in his urine, and treatment was stopped. One year later, he received a cadaver kidney. Patient K7 received three monthly courses of melpha-
15 March 1990 • Annals ofInternal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
457
Table 3. Imn:mnoglobulins in Light Chain and Light and Heavy Chain Deposition Dise< ases Patient
Serum Polyclonal
Biosynthetic Products
Urine Monoclonal
Kl K2
Low Low
IgG kappa Free kappa
Kappa Kappa
K3 K4 K5
Low Normal Low
Free kappa None None
K6 K7
ND Low
ND None
ND None Trace Kappa ND None
K8
Low
None
Kappa
LI L2 AK1
Normal Normal Low
None Free lambda IgA kappa
Lambda Lambda IgA kappa
GL1
Low
IgG lambda
Lambda
GL2
Low
IgG lambda
IgG lambda
ND* Kappa dimer, monomer, fragments ND Kappa monomer Kappa dimer, monomer, fragment ND Kappa dimer, monomer, fragment Kappa dimer, monomer, fragment ND ND Alpha fragment and multimers, free kappa G a m m a fragment, intact lambda and lambda fragments, polymers ND
* N D = not clone.
Ian and prednisone. During the third course, he had profound thrombocytopenia requiring platelet transfusions, and he refused further chemotherapy. His serum and urine contained no monoclonal protein at diagnosis. However, bone marrow analysis, which had shown monoclonal kappa production before therapy, indicated a marked reduction after the three treatment cycles. The same results were obtained in several studies done while he was on hemodialysis and after transplantation. However, 3 years after transplantation and 10 years after diagnosis, the amount of free kappa production increased, despite the continued administration of immunosuppressive agents. He subsequently died from systemic sepsis acquired during hospitalization for surgical treatment of peripheral arterial insufTable 4. Risnal Pathology in Light Chain and Light and Patient Glomeruli
ficiency, apparently unrelated to his primary disease. Patient AK1 received three different chemotherapeutic regimens. Initially, he received daily melphalan and prednisone with little response. He was subsequently given a 4-month course of carmustine, doxorubicin, vincristine, and prednisone with subjective but little objective improvement. He was then switched to cyclophosphamide (50 to 100 mg per day) and prednisone (10 mg per day) for a 7-month period. His abnormal serum and urine proteins gradually disappeared. His bone marrow analyses showed diminishing amounts of free light chains and alpha fragment and an increase in normal polyclonal immunoglobulin production which was reflected in quantitative normalization of his serum globulins. Patient GL2, whose
Heavy Chain Deposition 1Diseases
Light Microscopy Bence-Jones Casts
Amyloid
Immunofluorescence Glomerular Tubular Basement Basement Membrane Membrane
Kl K2 K3 K4 K5 K6
Normal Normal Normal Mesangial nodules Increased mesangium Normal
Yes Yes Yes Yes Yes No
No No No No No Yes
Kappa Kappa NDf Kappa Kappa Kappa
Kappa Kappa ND Kappa Kappa Kappa
K7
Mesangial nodules Sclerosis
No No No Yes
No No No Yes
Kappa
Kappa Kappa
ND
ND
No
No
Alpha, kappa
Focal
No No
No No
G a m m a , lambda G a m m a , lambda
Focal
K8J LI L2
AK1 GL1 GL2
Normal Increased mesangium, confluent deposits Mesangial nodules Confluent deposits
-
* G = graiHilar; F = fibrillar; C = conflueint. t N D = nc)t done. X See refere:nce 48.
458
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
diagnosis was established during investigation of asymptomatic proteinuria discovered during a routine physical examination, was treated with melphalan and prednisone (as above) for 1 year with reduction of her proteinuria to 0.6 g/d. At present, 4 of the 11 patients diagnosed clinically (Patients K4, K5, A K 1 , GL2) are living, up to 6 years from the time of diagnosis. Patients K5, K7, and AK1 received cadaveric renal transplants after periods of hemodialysis. Each was treated with chemotherapy before transplantation. In Patients K5 and A K 1 , the monoclonal protein disappeared from the serum and urine before transplantation; this disappearance was confirmed by repeat biosynthetic analysis in Patient AK1. Immunopathology Table 4 summarizes the pathologic findings in the 13 patients whose renal disease was classified as light chain or light and heavy chain deposition disease. Of the 11 renal biopsies examined with immunofluorescence, 10 had monoclonal immunoglobulin deposits that did not bind Congo Red. In 2 of the 13 patients, the diagnosis of light chain deposition disease was made retrospectively by electron microscopy of autopsy specimens that showed the distinctive clustered punctate deposits in glomerular and tubular basement membranes in the presence of multiple myeloma. One of these patients had free kappa chains in the serum, and the other had lambda light chains in both the serum and urine. Among the 11 patients examined by immunofluorescence, four different types of monoclonal deposits were found: 7 patients had kappa light chains; 1, lambda light chains; 1, alpha and kappa chains; and 2, both gamma and lambda chains. Hence, among our patients, the ratio of kappa to lambda producers was 9/4. Patients K6 and L2, in addition to
having the nonamyloid light chain deposition, had focal deposits of Congo Red binding material in renal blood vessels and myocardium. Patient K6 also had significant infiltration of the gastric wall with amyloid.
Biosynthetic Analysis Analyses of the immunoglobulins synthesized by aspirated bone marrow cells in short-term tissue culture were completed in seven of the patients (Table 3). All the patients synthesized immunoglobulin-related polypeptides corresponding to the class of molecule found in the tissue deposits. In two patients whose serum and urine contained no M-protein, the proteins synthesized by the cultured bone marrow cells were the only evidence of monoclonal immunoglobulin synthesis. Bone marrow cells from all but one patient contained, in addition to intact light chains (determined by their antigenicity and molecular mass), labeled polypeptides bearing light chain antigenic determinants that were shorter than expected for normal chains. Detailed analysis of the production of one such fragment, which represented a major cytoplasmic molecule, suggested a synthetic, not degradative, origin. In some cases, more than one such fragment could be identified. In Patients GL1 and A K l , whose deposits were stained with both antiheavy and antilight chain sera, the plasma cells produced labeled proteins that were precipitable with antibodies specific for the deposited heavy and light chain determinants. However, the molecular sizes of the labeled antigamma precipitable molecules in Patient GL1 and the anti-alpha precipitable species in Patient A K l indicated that the major intra- and extracellular immunoglobulins were covalently and noncovalently linked polymers of heavy chain fragments and light chains. The truncated heavy
Table 4. ,(Continued) Immunofluorescence Blood Vessels
Kappa Kappa ND Kappa Kappa Kappa
Amyloid P Component
-
Absent Absent ND ND ND ( + ) Amyloid, ( — )nonamyloid Absent ND Absent ( + )Amyloid, ( —)nonamyloid Absent
_ -
Absent Absent
Kappa
-
Lambda ND
Glomerular Basement Membrane and Mesangium
_
Electron Microscopy* Tubular Basement Membrane
G G G G
G G G G G
—
—
G
G G
-
Blood Vessels
-
_ G G G G F G
-
G
G
F
C
-
-
Minimal C
_ -
_ -
15 March 1990 • Annals of Internal Medicine • Volume 112 • Number 6
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/19700/ by a University of California San Diego User on 03/06/2017
459
chains also appeared to be synthetic, not proteolytic, products. Discussion Diagnosis of light chain deposition disease is made on the basis of the immunohistologic findings obtained when affected tissues from biopsy or autopsy are examined with reagents of demonstrable sensitivity and specificity. The deposits are nonCongophilic. Diffuse linear staining of glomerular and tubular basement membranes and vessels is seen only with antibody directed against a single class of immunoglobulin light chain. Kidney tissues from patients with light and heavy chain deposition disease, in addition to having glomerular staining for only one type of light chain, react strongly with antisera directed against the constant region determinants of a single heavy chain class. The tubular basement membranes and vessels are stained less uniformly, with focal rather than diffuse involvement. In contrast to immune complex diseases which have granular deposits containing immunoglobulins of both light chain classes and C3, there is usually little or no staining with reagents specific for complement components. The most frequent form of nonamyloid monoclonal immunoglobulin deposition is kappa light chain deposition disease. Lambda light chain deposition represents 1 5 % to 2 0 % and combined light and heavy chain deposition, fewer than 10% of the reported cases. Table 5 compares the clinical features of our 13 patients with those in cases reported elsewhere. In addition, we have compared the clinical features of our patients with those in cases of light chain amyloidosis reported from the Mayo Clinic (57, 58). The dominant feature in our patients with light chain and light and heavy chain deposition disease, as well as in such patients from other centers, was significant renal disease. Ninety-two percent of our patients and 9 4 % of those from elsewhere had renal insufficiency at diagnosis. Similar percentages of patients had substantial nep h r o p a t h y proteinuria in addition to the excretion of monoclonal immunoglobulins. A few patients had one
or the other. The proportion of patients with light chain amyloid and proteinuria at diagnosis was similar to that found in light chain deposition disease, but the proportion with azotemia at presentation was somewhat lower in the amyloid group. Microscopic hematuria occurred in at least 20% of the reported cases. Since many of the cases studied were described by nephrologists or nephropathologists, the data on renal manifestations were quite complete and the incidence probably reliable. Fewer data were available on other clinical aspects of the disease. Hypogammaglobulinemia was more frequent in our patients than in those from elsewhere (Table 6). Fully 67% of the New York University group had low levels of most or all classes of serum immunoglobulins, a fraction slightly higher than the 56% reported from other centers. We believe that hypogammaglobulinemia in a patient with substantial albuminuria strongly suggests some form of monoclonal immunoglobulin deposition disease. The proportion of our patients with monoclonal serum proteins was similar to that reported elsewhere; however, other centers reported a slightly larger percentage of patients with urinary monoclonal light chains. Patients with light chain amyloid showed similar percentages of monoclonal serum and urine immunoglobulin components. In approximately 20% of cases, no monoclonal immunoglobulins were detected by conventional analysis. Our work in both light chain and light and heavy chain deposition and light chain amyloid shows that, when examined using sensitive radiolabeling techniques, cells from such patients produce monoclonal immunoglobulin polypeptides of the same class as those deposited in the tissues (57). We and others (12, 26, 55) have previously suggested that some patients who appear to have nonsecretory myeloma may have various forms of immunoglobulin deposition disease in which the absolute rate of monoclonal immunoglobulin synthesis is low and the protein products have high tissue affinity. The incidence of multiple myeloma in patients with deposition disease may be higher than in those with light chain amyloid. Our criteria for diagnosis of mye-
Table 5. Clink :aJ Features in Light CIlain and Light and Heavy C hain Chain Amyloiciosis Series
Hypertension
Proteinuria
Azotemia
Depositkm Diseases C Compared with Those of Light
Cardiac Features
Hepatic Features
Gastrointestinal Neurologic Features Features
n/N ()
Light chain an
