1. Light chain deposition disease
R4 김슬기/Prof 정경환

2. Renal disease in multiple myeloma
Approximately 50% of Multiple Myeloma (MM) have renal impairment
Approximately 20 % plasma creatinine ≥2 mg/dL at presentation
Renal biopsy of patients with MM and renal disease
40-63%: cast nephropathy(myeloma kidney)
7-30%: amyloidosis
19-26%: light chain deposition disease
AL amyloidosis and light chain deposition disease
-typically present with the nephrotic syndrome
-rather than renal failure, as in myeloma kidney 2

3. Light chain deposition disease (LCDD)
Clonal plasma cell proliferative disorders
Monoclonal immunoglobulin deposition disease
Characterized by tissue deposits of light chain fragments
Leading to organ dysfunction
Multiple myeloma or waldenstrom macroglobulinemia
Pathology
Similar pathogenetically to AL amyloidosis
Light chain fragments do not have form amyloid fibrils
Non-amyloid monoclonal immunoglobulin light chain (usually kappa) deposition disease that is caused by a clonal plasma cell proliferative disorder (68 %)
Present with renal, cardiac, or hepatic involvement
Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis), light chain deposition disease (LCDD), and heavy chain deposition diseases (HCDD) are clonal plasma cell proliferative disorders characterized by tissue deposits of light chain or heavy chain fragments, leading to organ dysfunction. Heavy chain deposition disease and light chain deposition disease are collectively referred to as monoclonal immunoglobulin deposition disease. A minority of patients has or develops multiple myeloma or Waldenstrom macroglobulinemia 3

4. Light chain deposition disease (LCDD)
Median age at diagnosis for LCDD : 58 years
Representing a younger population when compared to MM
LCDD affects men 2.5 times more often than women
Clinical features
: proteinuria (97%), renal insufficiency (97%),
HTN (83%) ,haematuria (62%)
κ/λ sFLC ratio
abnormal all 51 patients (100%)
markedly abnormal (<0.125 or >8) in 78%
Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis), light chain deposition disease (LCDD), and heavy chain deposition diseases (HCDD) are clonal plasma cell proliferative disorders characterized by tissue deposits of light chain or heavy chain fragments, leading to organ dysfunction. Heavy chain deposition disease and light chain deposition disease are collectively referred to as monoclonal immunoglobulin deposition disease. A minority of patients has or develops multiple myeloma or Waldenstrom macroglobulinemia
Clin J Am Soc Nephrol 2011 4

5. Diagnosis
Figure 1. Diagnostic approach for LCDD. SPEP, serum electropho-
resis; FLC, free light chains; IFE, immunofixation; UPEP, urine
protein electrophoresis; GN, glo-merulonephritis; IC, immune
complexes; MM, multiple mye- loma; LCDD, light chain deposi-
tion disease.

6. Laboratory features of LCDD different from classical myeloma
-Serum total protein is normal to low
-Bence–jones protein(100% )
-Hypogammaglobulinemia
as opposed to hypergammaglobulinemia seen in classical MM
low molecular weight are easily filtered out by the kidneys
Many patients do not have a serum M (monoclonal) component
most light chains are quickly filtered by the kidneys
Urine immuno fixation electrophoresis reveals the type of monoclonal component (kappa: lambda ratio of 2:1)
-lambda LCDD has a three times worse prognosis than kappa LCDD

7. Serum protein eletrophoresis pattern
약 20여종의 아미노산으로 구성된 단백질은 Aminogroup(NH₂)과 Carboxylgroup (COOH)의 극성(polar)에 의한 양극성 전해질(amphoteric electrolyte)의 성질이 있으며 이에 따라 각각 고유의 등전점을 가지게 된다.   자신의 등전점보다 높은 pH에서는 음이온으로 하전되며 낮은 pH에서는 양이온으로 하전된다. 완충액의 pH 8.6에서 단백질은 음이온으로 하전된다. 이 음이온들을 하전 정도에 따라 양극쪽으로 다르게 영동하여 Albumin, α1-globulin, α2-globulin, β-globulin,γ-globulin의 분획을 얻는 방법이다.
2. 임상적의의
1)  Albumin 증가, globulin(-)
(i) 사구체성  단백뇨(혈장고분자 단백질의 대부분) : 급성사구체신염, 만성 사구체 신염, 신증후군, Lupus 신염.
(ii) 세뇨관성 단백뇨 (kappa, lambda type의 free light chain 이 많고 IgG의 Fa Fab fragment  2-microglobuiln이나, 1-microglobulin이 출현한 예도 있음) : 만성 cadmium중독, Wilson병, cystinosis, 신장이식.
2)  Albumin(저하)  M peak
: Bence-jonce proteinuria, Amyloidosis, macrogllobulin혈증
chronic inflammation :decreased albumin,
increased γ globulin
2. acute inflammation :increased α2 fraction(haptoglobin)
decreased C3
post spinal cord injury with hypoproteinemia of
several fraction

8. 1. 검사원리
약 20여종의 아미노산으로 구성된 단백질은 Aminogroup(NH₂)과 Carboxylgroup (COOH)의 극성(polar)에 의한 양극성 전해질(amphoteric electrolyte)의 성질이 있으며 이에 따라 각각 고유의 등전점을 가지게 된다.   자신의 등전점보다 높은 pH에서는 음이온으로 하전되며 낮은 pH에서는 양이온으로 하전된다. 완충액의 pH 8.6에서 단백질은 음이온으로 하전된다. 이 음이온들을 하전 정도에 따라 양극쪽으로 다르게 영동하여 Albumin, α1-globulin, α2-globulin, β-globulin,γ-globulin의 분획을 얻는 방법이다.
2. 임상적의의
* 각분획상에 따른 대표적 질환
 (1) 단백 부족형 (2) Nephrosis형 (3) 급성 간장애형 (4) 간경변
 (5) 급성염증형  (6) 만성염증형 (7) 분획 광역 증가형(8) M-단백혈증
 (9)  2 분획증가형 (10) 임신형 - 임신중독증 또는 기타합병증
 (11) 단백결핍형

9. Monoclonal pattern on serum protein electrophoresis (SPEP)
Monoclonal gammopathy on immunofixation
(A) Densitometer tracing of these findings reveals a tall, narrow-based peak (red asterisk) of gamma mobility and has been likened to a church spire. The monoclonal band has a densitometric appearance similar to that of albumin (alb) and a reduction in the normal polyclonal gamma band. (B) A dense, localized band (red asterisk) representing a monoclonal protein of gamma mobility is seen on serum protein electrophoresis on agarose gel (anode on left).
Reproduced with permission from: Kyle, RA, Rajkumar, SV. Plasma cell disorders. In: Cecil textbook of medicine, 22nd ed, Goldman, L, Ausiello, DA (Eds), WB Saunders, Philadelphia p Copyright © 2004 Elsevier
This figure shows the serum protein electrophoretic pattern (SPEP) and immunofixation pattern of a single serum sample with antisera to heavy chain determinants of IgG, IgA, and IgM, and to kappa and lambda light chains. It shows a discrete band on SPEP (red asterisk) and a band with similar mobility reacting only with the antisera to IgG (blue asterisk) and the kappa light chain (black asterisk), indicative of an IgG kappa monoclonal protein.
Reproduced with permission from: Kyle RA, Rajkumar SV. Plasma cell disorders. In: Cecil textbook of medicine, 22nd ed, Goldman L, Ausiello DA (Eds), WB Saunders, Philadelphia p Copyright © 2004 Elsevier.

10. Urine electorophoresis pattern
1. Severe proteinuria: glomerular nephropathy : major band albumin + transferrin
2. trace of proteinuria with faint band of albumin and other diffuse protein
3 imunoglobulin light chain
4 tubular proteinuira with multiple band
5 Hematuira with major band of hemoglobin
Urine electoro pattern]
1. severe glomerular preoteinuria magor band albumin + transferring
2 trace of proteinuria with faint band of albumin and other diffure protein
3 imglo light chin
4 tubular proteinuira with multiple band
Hematuirawith major band of hemoglobin
Serum and urine protein electophoretic pattern in a patient with multiple myeloma
Serum larger complete immunogloculine urine small amount of whole immunoglovulin

11. Urinary monoclonal protein Urinary monoclonal protein
Panel B: This figure illustrates the cellulose acetate electrophoretic pattern of a urine sample. It reveals a dense band of protein with beta mobility. Panel A: Densitometer tracing shows a tall, narrow-based peak of beta mobility. These findings are consistent with a urine monoclonal protein (Bence Jones protein); confirmation of the diagnosis requires demonstration that the protein contains only a lambda or kappa light chain with no heavy chain reactivity.
Immunofixation of a concentrated urine specimen from the previous patient with antisera to kappa and lambda light chains shows a discrete lambda band, indicating a monoclonal lambda light chain (ie, Bence Jones protein of lambda specificity).

12. Diagnosis
sFLC measurements are important in light chain deposition disease because:
- abnormal in 90% of patients at the time of diagnosis
-useful for monitoring disease progress
-identify patients who were previously unrecognised
sFLC testing alone, SPE and sFLC were both as sensitive (77.8%) for LCDD
-combine serum PEL, FLC and IFE, and urine PEL/IFE,
the sensitivity for LCDD goes up to 83.3%
Clin Chem 2009;55:
A series of 17 patients with biopsy-proven LCDD, sFLCs were abnormal with a clonal bias in 15 (88%) of the patients.
Of these, 11 (64%) patients had κ excess, 4 (23%) had λ excess while 2 (11%) had polyclonal increased FLCs.
median κ levels :317 mg/L (range 8.5-2,260)
median λ levels :64 mg/L (range 17-10,700)
sFLCs identified 33% more patients with LCDD than standard electrophoretic methods
Haematologica 2005;90:1414a
Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis), light chain deposition disease (LCDD), and heavy chain deposition diseases (HCDD) are clonal plasma cell proliferative disorders characterized by tissue deposits of light chain or heavy chain fragments, leading to organ dysfunction. Heavy chain deposition disease and light chain deposition disease are collectively referred to as monoclonal immunoglobulin deposition disease. A minority of patients has or develops multiple myeloma or Waldenstrom macroglobulinemia 12

13. Diagnostic sensitivity of the sFLC tests in LCDD
The above study by Katzmann et al. supports previous studies by the same authors in which the diagnostic sensitivity of the sFLC tests in LCDD were evaluated. In one of these, 17 of 19 patients with LCDD had an abnormal sFLC κ/λ ratio, including 7 patients who were negative by sIFE (Table 17.1 and Figure 17.1). One sample was falsely negative by sFLC analysis but positive by sIFE. In a subsequent publication, 7 further patients were studied and all had abnormal sFLC κ/λ ratios
Detection rates by sFLCs in 19 LCDD patients
sFLCs and serum and urine electrophoretic tests in 19 patients with LCDD.
Clin Chem 2005;51:878-81

14. Diagnosis
66-year-old man suffering from asthenia and anaemia was investigated for serum protein abnormalities. SPE, sIFE and uIFE tests showed no evidence of monoclonal immunoglobulins (Figure 17.2). Serum immunoglobulins were normal/low: IgG 8.5 g/L; IgA 0.4 g/L and IgM 0.2 g/L. However, sFLC concentrations were highly abnormal: κ 294 mg/L; λ 71.6 mg/L and κ/λ ratio 4.1. These results indicated a monoclonal gammopathy and renal impairment. FLC quantification allowed the depositing FLC to be easily identified and supported the clinical diagnosis of LCDD obtained by renal biopsy.
LCDD showing normal SPE (scanning densitometry) and IFE, but sFLCs were highly abnormal
(κ 294 mg/L: λ 71.6 mg/L and κ/λ ratio: 4.1). T: Protein stain.
Clin Chem 2004;50:F38a

15. Renal involvement of LCDD
light chains
-filtered by the glomeruli, reabsorbed in the proximal tubules
( via receptor mediated endocytosis)
kidney is a prominent target for the deposition of these light chains
Nephrotic syndrome or asymptomatic proteinuria with renal
Impairment, which may be rapidly progressive deposits in the tubular basement membranes and Bowman's capsule that may be more prominent than those in the glomeruli
Clinical presentation varies in part with the site of deposition
-glomerular deposition -nephrotic syndrome (similar to AL amyloidosis)
-tubular deposition -renal insufficiency and relatively mild proteinuria
LCDD vs AL amyloidosis
-higher plasma creatinine concentration (5.1 versus 2.4 mg/dL )
-lower rate of protein excretion (3.7 versus 6.9 g/day)
Immunoglobulin light chain (AL) amyloidosis (previously referred to as primary amyloidosis), light chain deposition disease (LCDD), and heavy chain deposition diseases (HCDD) are clonal plasma cell proliferative disorders characterized by tissue deposits of light chain or heavy chain fragments, leading to organ dysfunction. Heavy chain deposition disease and light chain deposition disease are collectively referred to as monoclonal immunoglobulin deposition disease. A minority of patients has or develops multiple myeloma or Waldenstrom macroglobulinemia 15

16. Light chain deposition disease
Light micrograph in light chain deposition disease reveals marked thickening of the tubular basement membranes (most prominent at the arrow) due to the deposition of PAS-positive light chain fragments.
Immunofluorescence microscopy in light chain deposition disease involving the kidney. There is intense staining with anti-kappa light chain antibodies along the tubular basement membranes.
Electron micrograph showing granular deposits (arrow) along the tubular basement membrane in light chain deposition disease. The appearance of these deposits is different from the fibrils seen in amyloidosis even though both types of deposits are composed of light chain fragments. 16

17. Light chain deposition disease in the liver and in small intestine
Medium power view of an immunoperoxidase stain of a liver biopsy shows kappa light chain deposition in a patient with light chain deposition disease. A stain for lambda light chains was negative.
Immunoperoxidase stain of a small intestinal biopsy from a patient with light chain deposition disease and malabsorption shows the presence kappa light chains; a stain for lambda light chains was negative.

18. Bone marrow in light chain deposition disease
Immunoperoxidase stain of a bone marrow biopsy from a patient with light chain deposition diesease shows the presence of cells with monoclonal kappa light chains (left panel) but not lambda light chains (right panel).
kappa light chains (+) lambda light chains(-)

19. Prognosis Median duration of survival : 4 years
After 27 months, 57% uremia / 59% died
prognostic factors for LCDD
Age, presence of plasma cell myeloma, extrarenal light chain deposition
Median time to end-stage renal disease (ESRD) :2.7 years
5-year ESRD-free survival: 37%
Am J Kidney Dis. 2003;42:1154–63
There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib and dexamethasone has also been examined
Bortezomib and dexamethasone
Bortezomib inhibits the NFkB pathway, decreases TGF-β1 levels and may down-regulate collagen and TIMP-1 production
Fig 3. Renal survival in 63 patients affected by LCDD 19

20. Fig 5. MM associated with LCDD to patient survival
Fig 6. extrarenal LC deposition to patient survival

21. Treatment
There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib and dexamethasone has also been examined
Bortezomib and dexamethasone
Bortezomib inhibits the NFkB pathway, decreases TGF-β1 levels and may down-regulate collagen and TIMP-1 production 21

22. Treatment There is no standard treatment for LCDD
MM associated with LCDD
-According to myeloma guidelines
Prognosis is generally poor
Lack of evidence to suggest maintenance therapy for patients with LCDD.
-Experience in mm indicates that chronic treatment the use of thalidomidtenance could be feasible to improve and stabilize LCDD response
Currently, suppression of light chain production should be the goal of therapy
to avoid further deposition in organs not yet affected
Use of ACE inhibitors to decrease proteinuria, and renal failure patients may
require some form of dialysis as a function replacement strategy
There is no standard treatment for LCDD. High-dose melphalan in conjunction with autologous stem cell transplantation has been used in some patients. A regimen of bortezomib and dexamethasone has also been examined
Bortezomib and dexamethasone
Bortezomib inhibits the NFkB pathway, decreases TGF-β1 levels and may down-regulate collagen and TIMP-1 production
There was no difference between MM and non-MM patients in terms of the choice for treatment versus no treatment (P = 0.16). The use of corticosteroids + alkylating agents was not different between the 2 groups (P = 0.58), but the patients with MM were significantly more likely to be treated with vincristine-doxorubicin-dexamethasone (VAD) or vincristine-doxorubicin-methylprednisolone (VAMP) chemotherapy (CT) (P = 0.007) and CT + plasmapheresis (P = 0.04). High-dose CT + autologous stem cell transplantation (SCT) was received by 5 patients (1 case of idiopathic LCDD and 4 cases of LCDD associated with MM). All of them had renal insufficiency at presentation, with median creatinine of 2.9 mg/dL (256.3 μmol/L) and 25th, 75th percentiles of 1.95, 4.25 mg/dL (172.4, μmol/L). Twenty-two of the 63 patients (35%) showed symptomatic extrarenal LC deposition during the course of LCDD, the frequency of which is shown in Fig 2 (there were no differences between the MM and non-MM patients, data not shown). 22