Long-Term Follow-Up and Response to Chemotherapy in Patients With Light-Chain Deposition Disease Raymond L. Heilman, MD, Jorge A. Velosa, MD, Keith E. Holley, MD, Kenneth P. Offord, MS, and Robert A. Kyle, MD • Nineteen patients with light-chain deposition disease (LCDD) were studied retrospectively. This report presents data on long-term patient and renal survival and the response to intermittent administration of melphalan and prednisone. Immunoelectrophoresis or immunofixation demonstrated a monoclonal protein in the serum of 78% and in the urine of 84% of the patients; 16% had no demonstrable monoclonal protein in serum or urine. The median age at presentation was 51 years (range, 37 to 77 years). Twelve (63%) of the patients had a monoclonal protein of undetermined significance without evidence of myeloma. The typical glomerular lesion was a diffuse mesangial nodular lesion that was positive for periodic acid-Schiff (PAS) stain with acute and chronic tubulointerstitial changes. Fifteen patients had K light-chain deposition and four had A light-chain deposition. Five-year actuarial patient survival and survival free of end-stage renal disease were 70% and 37%, respectively. Seventeen patients received melphalan and prednisone, and one patient received chlorambucil and prednisone. All of the patients had some impairment of renal function at presentation, and 58% had a serum creatinine concentration greater than 354 ~mol/L (4.0 mg/dL). There was either stabilization or improvement in renal function after chemotherapy in five of eight patients who had a serum creatinine concentration less than 354 ~mol/L (4.0 mg/dL) at the initiation of therapy. Of the 11 patients with a high serum creatinine concentration (>354 ~mol/dL [4.0 mg/dL)), 82% progressed to end-stage renal disease despite therapy. Follow-up urine protein studies demonstrated at least a 50% decrease in urine protein excretion in five of 15 patients. We conclude that in patients with LCDD and serum creatinine concentration less than 354 ~mol/L (4.0 mg/dL), intermittent administration of melphalan and prednisone may stabilize or improve renal function. © 1992 by the National Kidney Foundation,lnc. INDEX WORDS: Light-chain deposition disease.
L
IGHT-CHAIN deposition disease (LCDD) was recognized as an infiltration of light chain involving multiple organs by Randall et all in 1976. Renal disease, including renal insufficiency, proteinuria, and nephrotic syndrome, is the major manifestation of LCDD. Many cases are associated with mUltiple myeloma or lymphoproliferative disease, but up to 50% of patients have no evidence of a neoplastic plasma cell proliferation. I-6 Approximately 85% are associated with K light-chain deposition. A monoclonal protein of the same light-chain type is usually demonstrated in serum or urine, but approximately 25% of patients have no demonstrable light chain in serum or urine by immunoelectrophoresis or immunofixation. 3-5 Even in the absence of a
From the Section of Nephrology and Hypertension. Mayo Clinic Scottsdale. Scottsdale. AZ; and the Division of Nephrology and Internal Medicine. the Section of Medical Pathology. the Section of Biostatistics. and the Division of Hematology and Internal Medicine. Mayo Clinic and Mayo Foundation. Rochester. MN. Received September 6. 1991 .. accepted in revisedform March 2.1992. Address reprint requests to Raymond L. Heilman. MD. Mayo Clinic Scottsdale. 13400 E Shea Blvd. Scottsdale. AZ 85259. © 1992 by the National Kidney Foundation. Inc. 0272-6386/92/2001-0003$3.00/0 34
monoclonal light chain in serum or urine, immunofluorescence usually demonstrates a monoclonal population of plasma cells in the bone marrow of these patients. 5,7,8 The renal lesion is usually a nodular mesangial lesion that is often indistinguishable from diabetic lesions by light microscopy.I,9-12 Immunofluorescence and electron microscopy are essential in making the diagnosis, and the findings on renal biopsy are often the first evidence of LCDD. I,3-8,11.12 The frequency of LCDD is not known. In a renal biopsy study of 260 patients with idiopathic proteinuria, five patients had amyloid and seven patients had LCDD. 13 In a renal biopsy study by Pirani et aI, II of 47 patients with plasma cell dyscrasia, 24 had cast nephropathy and 10 had LCDD. The prognosis for renal function is usually poor, but long-term follow-up studies in LCDD are lacking. Most patients will progress to endstage renal disease if left untreated. The role of chemotherapy in preventing the progression of the renal lesion remains unclear. In an uncontrolled study by Ganeval et al, 3 five of six patients with LCDD treated with melphalan and prednisone had stabilization or improvement in renal function with a follow-up period of 21 to 42 months.
American Journal of Kidney Diseases, Vol XX, No 1 (July), 1992: pp 34-41
35
LIGHT-CHAIN DEPOSITION DISEASE
We studied 19 patients seen at our institution who had LCDD. The findings are presented in this report and include long-term patient and renal survival, as well as our experience with administration of melphalan and prednisone. METHODS We reviewed all cases from our renal pathology records from 1972 through May 1988 in which there was monoclonal light-chain deposition on immunofluorescent studies and a final diagnosis of LCDD. Criteria for inclusion in this study were evidence of nonamyloid monoclonal light-chain deposition in renal parenchyma by immunofluorescence, immunoperoxidase stain, or by electron microscopy, and evidence of monoclonal light-chain production. Evidence of monoclonal light-chain production required either the demonstration of a monoclonal light chain in urine or serum by immunoelectrophoresis or immunofixation, or the demonstration of a monoclonal population of plasma cells in the bone marrow by immunofluorescence or immunoperoxidase techniques. Methods of preparing renal tissue for light microscopy, immunofluorescence, and electron microscopy were as previously described. 14 Light microscopy preparations were studied for sclerotic glomeruli, mesangial expansion, mesangial proliferation, thickening of capillary loops, extracapillary proliferation, and tubulointerstitial and vascular changes. Each finding was scored by two of the investigators as absent, mild, moderate, or severe. Indirect immunofluorescent studies on frozen tissue were available in 10 patients, and indirect immunoperoxidase studies on paraffin-block sections with antibodies for light chain were performed in the remaining nine patients. Electron micrographs were analyzed for the presence, location, and ultrastructural characteristics of light-chain deposits. Clinical records were reviewed and pertinent clinical, laboratory, and follow-up data were abstracted. Additional followup information was obtained when necessary.
Immunoelectrophoresis and I mmunofixation Serum and urine protein immunoelectrophoresis was performed using monospecific antisera to IgG, IgA, IgM, IgD, and IgE, as well as to K and A light chains. Antisera from various sources were used to ensure antigenic recognition. Immunofixation was used when the results of immunoelectrophoresis were equivocal.15
Definition of Multiple Myeloma Minimal criteria for the diagnosis of mUltiple myeloma included bone marrow with 10% or more plasma cells, or histologic proof of a plasmacytoma plus one of the following: an M protein in the serum (usually >3 gjdL), an M protein in the urine, or lytic bone lesions. The patients had the usual clinical features of multiple myeloma. 16
Statistical Methods Statistical methods were limited to a descriptive display of findings and an actuarial estimator" of patient survival (death by any cause) after presentation (time zero). Additionally,
survival free of end-stage renal disease was estimated. For this, the earliest occurrence after presentation of any of the following was considered failure: initiation of chronic hemodialysis, renal transplantation, or death.
RESULTS
Clinical and Laboratory Findings at Presentation
Nineteen patients met the criteria for this study. There were 12 men and seven women. The median age at presentation was 51 years (range, 37 to 77 years). Findings on physical examination were nonspecific (Table 1). Hypertension was present in 12 patients (63%). Four patients had findings of congestive heart failure. Congo red staining for amyloid deposits in tissue from renal biopsies was negative in all four of these patients; in two patients, tissue from right ventricular endomyocardial biopsies was also negative for amyloid deposits. Two patients had peripheral neuropathy and one patient had a spastic dysphonia of long duration. Amyloid stains of renal tissue were Table 1. Clinical Characteristics at Presentation in 19 Patients With LCDD Findings
Renal presentation Renal insufficiency Nephrotic proteinuria (urine protein, >3.5 g/d) Asymptomatic proteinuria Acute renal failure Acute glomerulonephritis Physical examination Hypertension (> 150/95 mm Hg or on treatment) Peripheral edema Neuropathy Congestive heart failure Laboratory findings Anemia (hemoglobin < 110 gIL) Serum creatinine (~mol/L) 354 (4 mg/dL) Serum calcium > 2.52 mmol/L (10.1 mg/dL) Dialysis Microscopic hematuria (>5 erythrocytes/HPF) Abbreviation: HPF, high-power field .
No. of Patients
%of Total
11 10 10 1 2 1
58 53 53 5 11 5
12 5 2 4
26 11 21
15
79
2 8 9
11 42 47
2 3
11 16
11
58
63
36
HEILMAN ET AL
Table 2. Results of Immunoelectrophoresis and Immunofixation in 19 Patients With LCDD No. of Patients Immunoglobulin
Serum
Urine
IgG-K Free K IgA-K IgG-X IgA-X Free X IgM-K Negative Not done
5
4 8
3
1
1
5'
0 3 0
, IgG-X protein demonstrated after 5 years of follow-up in one case.
negative in both patients with peripheral neuropathy, and electron microscopy of renal tissue did not show amyloid deposits. Serum protein electrophoresis detected an M spike in only five patients (26%). Hypogammaglobulinemia was found in nine patients. Immunoelectrophoresis (or immunofixation) demonstrated a monoclonal protein in the serum of 14 of 18 patients (78%) and in the urine of 16 of 19 patients (84%). Table 2 identifies the specific findings of the immunoelectrophoresis or immunofixation of serum and urine proteins. Three patients (16%) had no demonstrable monoclonal protein in either serum or urine during their initial presentation and treatment. One of these three patients (patient 7) had a small serum monoclonal IgG-A protein after 72 months of follow-up. Ten patients had greater than 10% plasma cells in the bone marrow aspirate. Eleven of 19 patients had bone marrow immunoperoxidase studies. Ten patients had predominantly K lightchain-positive plasma cells, and one had predominantly A staining. Four patients had multiple myeloma, one probably had myeloma, and one had smoldering myeloma. One had a malignant lymphoproliferative process. The remaining 12 patients had a monoclonal gammopathy of undetermined significance and did not have multiple myeloma. Two patients had mild hypercalcemia (2.62 and 2.69 mmol/L [10.5 and 10.8 mg/dLD at presentation. However, this did not appear to be a clinically significant factor in their subsequent renal course or outcome.
Pathologic Renal Findings
Mesangial expansion with eosinophilic material positive for periodic acid-Schiff (PAS) stain was the predominant lesion in 17 of the 19 patients. Acute and chronic tubulointerstitial changes were a prominent characteristic of the renal abnormality. Eosinophilic thickening of the tubular basement membrane was apparent in 58% of patients. Congo red staining of renal tissue was negative for amyloid in all 11 cases tested. Immunofluorescence and immunoperoxidase studies and electron microscopy findings were characteristic and helped confirm the diagnosis of LCDD (Table 3). Patient and Renal Survival
Patient survival was 89% at 1 year and 70% at 5 years. Survival free of end-stage renal disease was 67% and 37% at 1 and 5 years, respectively (Figs 1 and 2). When the latest date of either presentation or biopsy was used as time zero, the 1Table 3. Renal Biopsy Findings in 19 Patients With LCDD Findings Light microscopy Mesangial expansions Well-developed mesangial nodules Membranoproliferative glomerulonephritis Moderate to severe tubulointerstitial nephritis Moderate to severe tubular atrophy Tubular basement membrane thickening Moderate to severe vascular sclerosis Immunofluorescence (10 patients) and immunoperoxidase (9 patients) K light chain X light chain Glomerular basement membrane only Tubular basement membrane only Both glomerular and tubular basement membranes Other immunoreactive protein Electron microscopy Mesangial deposits Glomerular basement membrane deposits Tubular basement membrane deposits
No. of Patients
%of Total
17 11
89 58
4
21
10 16
53 84
11
58
15
79
15 4 2 2
79 21 11 11
15 9
79 47
17
89
18
95
16
84
37
LIGHT-CHAIN DEPOSITION DISEASE 100
80
(13) (9)
~
~
(7)
60
:0
III D
e
40
-
Q.
Expected Observed ( ) Numbers at risk
20 0
0
3
2
4
5
Years
Fig 1. Patient survival (Kaplan-Meier method) after presentation with light chain deposition disease (n = 19). Observed patient survival (heavy line) and expected patient survival (light line) for persons in general population of similar age, sex, and date of birth. Numbers in parentheses are the numbers of patients alive and being monitored at yearly points.
and 5-year rates changed slightly: patient survival was 89% and 71 %, and survival free of end-stage renal disease was 65% and 40%. Effects of Treatment on Serum and Urine Proteins Seventeen patients received two to 18 treatment cycles of melphalan and prednisone over a range of 3 to 42 months. One patient (patient 6) received placebo in a controlled trial. One patient with lymphoproliferative disease (patient 11) received chlorambucil for 51 months for a total dose of 2,749 mg. Nine patients received chemotherapy for 1 year or more. In the nine patients who received chemotherapy for more than 1 year, the serum M protein decreased in two, was stable in three (one of these was treated with chlorambucil and prednisone), and was not detectable in four at the onset of treatment. The urine M protein decreased in five patients (one patient was treated with chlorambucil and prednisone), remained stable in two, and was not detectable in two. Myelodysplasia or acute leukemia did not develop in any patient. Follow-up urine protein studies demonstrated a 50% or greater decrease in urine protein excretion in five of 15 patients. Proteinuria in the nephrotic range decreased to less than 1 g/d in two patients. In none of the 12 patients did monoclonal gammopathy of undetermined significance evolve into multiple myeloma or a malignant lymphoproliferative disorder during follow-up.
Treatment and Follow-Up of Renal Function Follow-up data are presented in three groups based on the serum creatinine concentration at the initiation of therapy (Table 4, Fig 3). Table 4 provides data on chemotherapy including the agents used, length of therapy, and total cumulative dose of melphalan or chlorambucil. Table 4 also includes patient status and renal function at last follow-up. None of the patients were known to be taking nonsteroidal antiinflammatory drugs or other nephrotoxins that would confuse interpretation of apparent changes in renal function. Group I includes seven patients who had a serum creatinine concentration greater than or equal to 884 ~molfL (10.0 mgjdL) or who required dialysis at the initiation of chemotherapy (Table 4). The mean length of follow-up in this group was 41 months. One patient (patient 10) with multiple myeloma and acute renal failure was treated with plasmapheresis for 2 weeks, followed by melphalan and prednisone for 27 months. This patient had improvement in renal function, with a stable serum creatinine concentration of 177 ~molfL (2.0 mg/dL) after 37 months of follow-up. The remaining six patients progressed to end-stage renal disease. One of these six patients did not receive chemotherapy, while the other five patients received chemotherapy for 1 t05 months (which is probably an inadequate length of treatment). Two patients died of complications related to their disease. Group II includes the four patients who had a 100(19)
80 ~
~
60
:0 III
D
e
40
(4)
(3)
(2)
3
4
5
Q.
-
20 0
Observed
( ) Numbers at risk
0
2
Years
Fig 2. Survival (Kaplan-Meier method) free of endstage renal disease in patients with light-chain deposition disease (n = 19). Numbers in parentheses are the numbers of patients alive without prior end-point at yearly observation points.
HEILMAN ET AL
38
Table 4. Response to Treatment Based on Serum Creatinine at Initiation of Therapy Treatment
Patients
Serum Cr at Presentation, I'mol/L (mg/dL)
Chemotherapy
Cumulative Melphalan Dose (mg)
Last Follow-Up (mo)
Duration (mo)
Group I (serum Cr concentration ~ 884 ILmoi/L or dialysis-dependent) 1 981 (11.1) MP 182 3 928 (10.5) 6 937 (10.6) MP 24 9 1 10 893 (10.1) MP 854 27 12 MHO MP 154 5 13 MHO MP 25 1 16 MHO MP 152 3 Group II (serum Cr concentration 354 to 883 ILmol/L) 407 (4.6) 2 MP 308 13 4 416 (4.7) MP 532 15 14 371 (4.2) MP 730 22 15 354 (4.0) MP 2 98 Group III (serum Cr concentration
L
IGHT-CHAIN deposition disease (LCDD) was recognized as an infiltration of light chain involving multiple organs by Randall et all in 1976. Renal disease, including renal insufficiency, proteinuria, and nephrotic syndrome, is the major manifestation of LCDD. Many cases are associated with mUltiple myeloma or lymphoproliferative disease, but up to 50% of patients have no evidence of a neoplastic plasma cell proliferation. I-6 Approximately 85% are associated with K light-chain deposition. A monoclonal protein of the same light-chain type is usually demonstrated in serum or urine, but approximately 25% of patients have no demonstrable light chain in serum or urine by immunoelectrophoresis or immunofixation. 3-5 Even in the absence of a
From the Section of Nephrology and Hypertension. Mayo Clinic Scottsdale. Scottsdale. AZ; and the Division of Nephrology and Internal Medicine. the Section of Medical Pathology. the Section of Biostatistics. and the Division of Hematology and Internal Medicine. Mayo Clinic and Mayo Foundation. Rochester. MN. Received September 6. 1991 .. accepted in revisedform March 2.1992. Address reprint requests to Raymond L. Heilman. MD. Mayo Clinic Scottsdale. 13400 E Shea Blvd. Scottsdale. AZ 85259. © 1992 by the National Kidney Foundation. Inc. 0272-6386/92/2001-0003$3.00/0 34
monoclonal light chain in serum or urine, immunofluorescence usually demonstrates a monoclonal population of plasma cells in the bone marrow of these patients. 5,7,8 The renal lesion is usually a nodular mesangial lesion that is often indistinguishable from diabetic lesions by light microscopy.I,9-12 Immunofluorescence and electron microscopy are essential in making the diagnosis, and the findings on renal biopsy are often the first evidence of LCDD. I,3-8,11.12 The frequency of LCDD is not known. In a renal biopsy study of 260 patients with idiopathic proteinuria, five patients had amyloid and seven patients had LCDD. 13 In a renal biopsy study by Pirani et aI, II of 47 patients with plasma cell dyscrasia, 24 had cast nephropathy and 10 had LCDD. The prognosis for renal function is usually poor, but long-term follow-up studies in LCDD are lacking. Most patients will progress to endstage renal disease if left untreated. The role of chemotherapy in preventing the progression of the renal lesion remains unclear. In an uncontrolled study by Ganeval et al, 3 five of six patients with LCDD treated with melphalan and prednisone had stabilization or improvement in renal function with a follow-up period of 21 to 42 months.
American Journal of Kidney Diseases, Vol XX, No 1 (July), 1992: pp 34-41
35
LIGHT-CHAIN DEPOSITION DISEASE
We studied 19 patients seen at our institution who had LCDD. The findings are presented in this report and include long-term patient and renal survival, as well as our experience with administration of melphalan and prednisone. METHODS We reviewed all cases from our renal pathology records from 1972 through May 1988 in which there was monoclonal light-chain deposition on immunofluorescent studies and a final diagnosis of LCDD. Criteria for inclusion in this study were evidence of nonamyloid monoclonal light-chain deposition in renal parenchyma by immunofluorescence, immunoperoxidase stain, or by electron microscopy, and evidence of monoclonal light-chain production. Evidence of monoclonal light-chain production required either the demonstration of a monoclonal light chain in urine or serum by immunoelectrophoresis or immunofixation, or the demonstration of a monoclonal population of plasma cells in the bone marrow by immunofluorescence or immunoperoxidase techniques. Methods of preparing renal tissue for light microscopy, immunofluorescence, and electron microscopy were as previously described. 14 Light microscopy preparations were studied for sclerotic glomeruli, mesangial expansion, mesangial proliferation, thickening of capillary loops, extracapillary proliferation, and tubulointerstitial and vascular changes. Each finding was scored by two of the investigators as absent, mild, moderate, or severe. Indirect immunofluorescent studies on frozen tissue were available in 10 patients, and indirect immunoperoxidase studies on paraffin-block sections with antibodies for light chain were performed in the remaining nine patients. Electron micrographs were analyzed for the presence, location, and ultrastructural characteristics of light-chain deposits. Clinical records were reviewed and pertinent clinical, laboratory, and follow-up data were abstracted. Additional followup information was obtained when necessary.
Immunoelectrophoresis and I mmunofixation Serum and urine protein immunoelectrophoresis was performed using monospecific antisera to IgG, IgA, IgM, IgD, and IgE, as well as to K and A light chains. Antisera from various sources were used to ensure antigenic recognition. Immunofixation was used when the results of immunoelectrophoresis were equivocal.15
Definition of Multiple Myeloma Minimal criteria for the diagnosis of mUltiple myeloma included bone marrow with 10% or more plasma cells, or histologic proof of a plasmacytoma plus one of the following: an M protein in the serum (usually >3 gjdL), an M protein in the urine, or lytic bone lesions. The patients had the usual clinical features of multiple myeloma. 16
Statistical Methods Statistical methods were limited to a descriptive display of findings and an actuarial estimator" of patient survival (death by any cause) after presentation (time zero). Additionally,
survival free of end-stage renal disease was estimated. For this, the earliest occurrence after presentation of any of the following was considered failure: initiation of chronic hemodialysis, renal transplantation, or death.
RESULTS
Clinical and Laboratory Findings at Presentation
Nineteen patients met the criteria for this study. There were 12 men and seven women. The median age at presentation was 51 years (range, 37 to 77 years). Findings on physical examination were nonspecific (Table 1). Hypertension was present in 12 patients (63%). Four patients had findings of congestive heart failure. Congo red staining for amyloid deposits in tissue from renal biopsies was negative in all four of these patients; in two patients, tissue from right ventricular endomyocardial biopsies was also negative for amyloid deposits. Two patients had peripheral neuropathy and one patient had a spastic dysphonia of long duration. Amyloid stains of renal tissue were Table 1. Clinical Characteristics at Presentation in 19 Patients With LCDD Findings
Renal presentation Renal insufficiency Nephrotic proteinuria (urine protein, >3.5 g/d) Asymptomatic proteinuria Acute renal failure Acute glomerulonephritis Physical examination Hypertension (> 150/95 mm Hg or on treatment) Peripheral edema Neuropathy Congestive heart failure Laboratory findings Anemia (hemoglobin < 110 gIL) Serum creatinine (~mol/L) 354 (4 mg/dL) Serum calcium > 2.52 mmol/L (10.1 mg/dL) Dialysis Microscopic hematuria (>5 erythrocytes/HPF) Abbreviation: HPF, high-power field .
No. of Patients
%of Total
11 10 10 1 2 1
58 53 53 5 11 5
12 5 2 4
26 11 21
15
79
2 8 9
11 42 47
2 3
11 16
11
58
63
36
HEILMAN ET AL
Table 2. Results of Immunoelectrophoresis and Immunofixation in 19 Patients With LCDD No. of Patients Immunoglobulin
Serum
Urine
IgG-K Free K IgA-K IgG-X IgA-X Free X IgM-K Negative Not done
5
4 8
3
1
1
5'
0 3 0
, IgG-X protein demonstrated after 5 years of follow-up in one case.
negative in both patients with peripheral neuropathy, and electron microscopy of renal tissue did not show amyloid deposits. Serum protein electrophoresis detected an M spike in only five patients (26%). Hypogammaglobulinemia was found in nine patients. Immunoelectrophoresis (or immunofixation) demonstrated a monoclonal protein in the serum of 14 of 18 patients (78%) and in the urine of 16 of 19 patients (84%). Table 2 identifies the specific findings of the immunoelectrophoresis or immunofixation of serum and urine proteins. Three patients (16%) had no demonstrable monoclonal protein in either serum or urine during their initial presentation and treatment. One of these three patients (patient 7) had a small serum monoclonal IgG-A protein after 72 months of follow-up. Ten patients had greater than 10% plasma cells in the bone marrow aspirate. Eleven of 19 patients had bone marrow immunoperoxidase studies. Ten patients had predominantly K lightchain-positive plasma cells, and one had predominantly A staining. Four patients had multiple myeloma, one probably had myeloma, and one had smoldering myeloma. One had a malignant lymphoproliferative process. The remaining 12 patients had a monoclonal gammopathy of undetermined significance and did not have multiple myeloma. Two patients had mild hypercalcemia (2.62 and 2.69 mmol/L [10.5 and 10.8 mg/dLD at presentation. However, this did not appear to be a clinically significant factor in their subsequent renal course or outcome.
Pathologic Renal Findings
Mesangial expansion with eosinophilic material positive for periodic acid-Schiff (PAS) stain was the predominant lesion in 17 of the 19 patients. Acute and chronic tubulointerstitial changes were a prominent characteristic of the renal abnormality. Eosinophilic thickening of the tubular basement membrane was apparent in 58% of patients. Congo red staining of renal tissue was negative for amyloid in all 11 cases tested. Immunofluorescence and immunoperoxidase studies and electron microscopy findings were characteristic and helped confirm the diagnosis of LCDD (Table 3). Patient and Renal Survival
Patient survival was 89% at 1 year and 70% at 5 years. Survival free of end-stage renal disease was 67% and 37% at 1 and 5 years, respectively (Figs 1 and 2). When the latest date of either presentation or biopsy was used as time zero, the 1Table 3. Renal Biopsy Findings in 19 Patients With LCDD Findings Light microscopy Mesangial expansions Well-developed mesangial nodules Membranoproliferative glomerulonephritis Moderate to severe tubulointerstitial nephritis Moderate to severe tubular atrophy Tubular basement membrane thickening Moderate to severe vascular sclerosis Immunofluorescence (10 patients) and immunoperoxidase (9 patients) K light chain X light chain Glomerular basement membrane only Tubular basement membrane only Both glomerular and tubular basement membranes Other immunoreactive protein Electron microscopy Mesangial deposits Glomerular basement membrane deposits Tubular basement membrane deposits
No. of Patients
%of Total
17 11
89 58
4
21
10 16
53 84
11
58
15
79
15 4 2 2
79 21 11 11
15 9
79 47
17
89
18
95
16
84
37
LIGHT-CHAIN DEPOSITION DISEASE 100
80
(13) (9)
~
~
(7)
60
:0
III D
e
40
-
Q.
Expected Observed ( ) Numbers at risk
20 0
0
3
2
4
5
Years
Fig 1. Patient survival (Kaplan-Meier method) after presentation with light chain deposition disease (n = 19). Observed patient survival (heavy line) and expected patient survival (light line) for persons in general population of similar age, sex, and date of birth. Numbers in parentheses are the numbers of patients alive and being monitored at yearly points.
and 5-year rates changed slightly: patient survival was 89% and 71 %, and survival free of end-stage renal disease was 65% and 40%. Effects of Treatment on Serum and Urine Proteins Seventeen patients received two to 18 treatment cycles of melphalan and prednisone over a range of 3 to 42 months. One patient (patient 6) received placebo in a controlled trial. One patient with lymphoproliferative disease (patient 11) received chlorambucil for 51 months for a total dose of 2,749 mg. Nine patients received chemotherapy for 1 year or more. In the nine patients who received chemotherapy for more than 1 year, the serum M protein decreased in two, was stable in three (one of these was treated with chlorambucil and prednisone), and was not detectable in four at the onset of treatment. The urine M protein decreased in five patients (one patient was treated with chlorambucil and prednisone), remained stable in two, and was not detectable in two. Myelodysplasia or acute leukemia did not develop in any patient. Follow-up urine protein studies demonstrated a 50% or greater decrease in urine protein excretion in five of 15 patients. Proteinuria in the nephrotic range decreased to less than 1 g/d in two patients. In none of the 12 patients did monoclonal gammopathy of undetermined significance evolve into multiple myeloma or a malignant lymphoproliferative disorder during follow-up.
Treatment and Follow-Up of Renal Function Follow-up data are presented in three groups based on the serum creatinine concentration at the initiation of therapy (Table 4, Fig 3). Table 4 provides data on chemotherapy including the agents used, length of therapy, and total cumulative dose of melphalan or chlorambucil. Table 4 also includes patient status and renal function at last follow-up. None of the patients were known to be taking nonsteroidal antiinflammatory drugs or other nephrotoxins that would confuse interpretation of apparent changes in renal function. Group I includes seven patients who had a serum creatinine concentration greater than or equal to 884 ~molfL (10.0 mgjdL) or who required dialysis at the initiation of chemotherapy (Table 4). The mean length of follow-up in this group was 41 months. One patient (patient 10) with multiple myeloma and acute renal failure was treated with plasmapheresis for 2 weeks, followed by melphalan and prednisone for 27 months. This patient had improvement in renal function, with a stable serum creatinine concentration of 177 ~molfL (2.0 mg/dL) after 37 months of follow-up. The remaining six patients progressed to end-stage renal disease. One of these six patients did not receive chemotherapy, while the other five patients received chemotherapy for 1 t05 months (which is probably an inadequate length of treatment). Two patients died of complications related to their disease. Group II includes the four patients who had a 100(19)
80 ~
~
60
:0 III
D
e
40
(4)
(3)
(2)
3
4
5
Q.
-
20 0
Observed
( ) Numbers at risk
0
2
Years
Fig 2. Survival (Kaplan-Meier method) free of endstage renal disease in patients with light-chain deposition disease (n = 19). Numbers in parentheses are the numbers of patients alive without prior end-point at yearly observation points.
HEILMAN ET AL
38
Table 4. Response to Treatment Based on Serum Creatinine at Initiation of Therapy Treatment
Patients
Serum Cr at Presentation, I'mol/L (mg/dL)
Chemotherapy
Cumulative Melphalan Dose (mg)
Last Follow-Up (mo)
Duration (mo)
Group I (serum Cr concentration ~ 884 ILmoi/L or dialysis-dependent) 1 981 (11.1) MP 182 3 928 (10.5) 6 937 (10.6) MP 24 9 1 10 893 (10.1) MP 854 27 12 MHO MP 154 5 13 MHO MP 25 1 16 MHO MP 152 3 Group II (serum Cr concentration 354 to 883 ILmol/L) 407 (4.6) 2 MP 308 13 4 416 (4.7) MP 532 15 14 371 (4.2) MP 730 22 15 354 (4.0) MP 2 98 Group III (serum Cr concentration
