AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Background

Light-chain deposition disease (LCDD) is the deposition of monoclonal, amorphous, noncongophilic light chains in multiple organs that do not exhibit a fibrillar structure when examined ultrastructurally.^{1, 2, 3}

In 1976, Randall et al recognized LCDD as an infiltration of light chains involving multiple organs.⁴ Renal involvement is a constant feature which include renal insufficiency, proteinuria, and nephrotic syndrome. Extrarenal involvement is primarily noted at autopsy and is usually confined to the perivascular regions of the affected organs. Approximately 50-60% of patients with LCDD have associated lymphoproliferative disorder, most commonly multiple myeloma. The remaining cases develop LCDD in the setting of progression of monoclonal gammopathy of unknown significance (MGUS) or with no evidence of neoplastic plasma cell proliferation.

Approximately 85% of cases are associated with kappa light-chain deposition.^{5, 6} 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. Even in the absence of a monoclonal light chain in serum or urine, immunofluorescence usually demonstrates a monoclonal population of plasma cells in the bone marrow of these patients.

The renal lesion is usually a nodular mesangial lesion that is often indistinguishable from diabetic lesions by light microscopy. Immunofluorescence and electron microscopy are essential in making the diagnosis, and the findings on renal biopsy are often the first evidence of LCDD.^{7, 8, 9, 10, 11}

The frequency of LCDD is unknown. Treatment with high-dose chemotherapy with or without autologous stem cell transplantation may result in disease stabilization and/or improvement in end-organ damage.^{1, 9, 12, 13, 14}

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Kidneys and Urinary System Center. Also, see eMedicine's patient education article Myeloma.

Related eMedicine topics:
Light Chain-Associated Renal Disorders
Multiple Myeloma [in the Radiology section]
Renal Failure, Chronic and Dialysis Complications

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Resource Center Cancer: Biologic Therapies
Resource Center Diabetic Microvascular Complications
Specialty Site Hematology-Oncology
Specialty Site Nephrology
CME Highlights From the American Society of Hematology 49th Annual Meeting and Exposition: Multiple Myeloma Update
CME/CE Multiple Myeloma: Determining Prognosis and Choosing Therapy (Slides With Transcript)
CME/CE Multiple Myeloma: Optimizing Care Across the Disease Spectrum

Pathophysiology

LCDD is characterized by deposition of monoclonal, amorphous light chains. Sites of light-chain deposition include the kidney, liver, heart, small intestine, spleen, skin, nervous system, and bone marrow.^{4, 13, 15, 16} The histologic appearance can mimic immunoglobulin-related amyloidosis (AL-amyloidosis), causing considerable diagnostic challenge.¹⁷ However, unlike AL amyloidosis, LCDD deposits lack the beta-pleated configuration, with no affinity for Congo red stain. Immunofluorescence of the bone marrow usually demonstrates a monoclonal population of plasma cells, and the characteristic "apple green" birefringence of amyloid is not observed under polarization.

AL-amyloidosis consists predominantly of lambda light chains, whereas kappa light chains dominate LCDD lesions. Electron microscopy is helpful in distinguishing between both these lesions. Amyloid deposits are characteristically fibrillar, whereas the LCDD deposits are ultrastructurally granular.^{5, 7, 8, 9, 10, 11, 18, 19, 20}

A study by Keeling et al revealed that altered expression of matrix metalloproteinases (MMPs), a group of enzymes with diverse proteolytic activities, occurs in LCDD and, to a greater degree, in amyloidosis.²¹

Renal involvement in the form of proteinuria or renal insufficiency is the most common manifestation. The renal lesion is usually a nodular glomerulosclerosis that mimics the Kimmelstiel-Wilson disease of diabetic nephropathy by light microscopy. Sites of deposit in the kidney can vary and include the glomeruli, tubular basement membrane, and Bowman capsule. Cases of LCDD have been reported to occur in patients with renal allografts, either de novo or in patients with a previous history of LCDD. 

Approximately 25% of patients with LCDD have cardiac and liver involvement. The cardiac manifestations include cardiomyopathy, congestive heart failure, and arrhythmias. The deposits in the liver are usually confined to the sinusoids and basement membrane of biliary ducts without associated parenchymal lesions. These patients are usually asymptomatic, with mild to moderate liver function abnormalities. Hepatomegaly may or may not be present. However, hepatic failure and portal hypertension may supervene in a small number of cases. 
 
Although pulmonary LCDD is rare, Bhargava et al reported 5 new cases that included both the nodular and diffuse forms parallel to AL-amyloidosis.²² Colombat et al also reported a new form of LCDD that presented as a severe cystic lung disorder requiring lung transplantation.²³ This entity was derived from unmutated B cells with a stereotyped IGHV4-34/IGKV1 receptor.

Occasionally, peripheral nerves are affected, resulting in polyneuropathy, However, a case of LCDD restricted to the brain was reported by Popovic et al wherein the periventricular foci of intracerebral vessels were overloaded with amorphous, eosinophilic material that stained for lambda light chains.¹⁶

Frequency

United States

The frequency of LCDD is unknown. In a renal biopsy study by Mallick et al of 260 patients with idiopathic proteinuria, 5 had LCDD.²⁴ A renal biopsy study by Pirani et al reported 47 patients with plasma cell dyscrasia, in whom 24 had cast nephropathy and 10 had LCDD.²⁵ The disease is found in approximately 5% of patients with multiple myeloma at autopsy.

Mortality/Morbidity

Most of the morbidity that is associated with LCDD is related to renal failure manifesting as nephrotic syndrome and its clinical sequelae. Liver dysfunction can also occur, with progression to hepatic failure. Other symptoms of LCDD relate to congestive heart failure, peripheral neuropathy, and skin lesions secondary to the deposition of light chains.¹⁵ LCDD may occasionally complicate Waldenström's macroglobulinemia, chronic lymphocytic leukemia, and nodal marginal zone lymphoma.

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Specialty Site Cardiology
Specialty Site Dermatology
Specialty Site Gastroenterology
Specialty Site Hematology-Oncology
Specialty Site Nephrology
Specialty Site Neurology & Neurosurgery

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

History

• Patients are found to have LCDD when they are evaluated for proteinuria or nephrotic syndrome by renal biopsy.
• The chief symptoms and signs are related to associated organ involvement and may manifest as renal failure, congestive heart failure, and/or liver failure.
• Most patients present with advanced disease due to a delay in the diagnosis.

Physical

Patients may present with end organ damage, which chiefly manifests as hypertension, peripheral edema, neuropathy, or congestive heart failure.²⁶ Approximately 50% of patients with LCDD present with nephrotic syndrome. However, in a quarter of patients, the proteinuria is less than 1 g per day as a result of tubulointestitial involvement.

Causes

Specific etiology is unknown.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Lab Studies

The laboratory workup for LCDD includes the following:

• Routine serum chemistries to evaluate hepatic and renal function
• Complete blood cell (CBC) count to assess for anemia
• Serum and urine electrophoresis with immunofixation to evaluate for a monoclonal protein
• Repeated studies of serum and urine protein with immunoelectrophoresis or immunofixation, if necessary, to demonstrate the presence of a small amount of monoclonal protein
• • In a minority of patients, a monoclonal protein may never be found in either serum or urine.
• Sensitive nephelometric immunoassays (NIAs) are now available for the detection of serum free light chains. These methods are also useful to detect response to therapy and to monitor disease activity as well as early relapse.
• • Kaplan et al have a developed a method to Isolate and biochemically characterize plasma monoclonal free light chains in amyloidosis and multiple myeloma.²⁷ It is possible that this procedure may be applied to reveal distinguishing chemical features of free light chains in serum, which in turn may predict the pathologic form of disease and yield information that could aid clinicians to better understand the mechanism(s) involved in the deposition of light chains in tissues.

Related Medscape topic:
Specialty Site Pathology & Lab Medicine

Imaging Studies

• Echocardiogram in cases of cardiac involvement

Procedures

• Biopsy of the specific organ suspected of involvement, with immunohistochemical staining for kappa and lambda chains
• Rectal biopsy or subcutaneous fat aspiration to exclude amyloidosis
• Bone marrow aspiration/biopsy to rule out multiple myeloma

Histologic Findings

The electron microscopic changes characteristic of LCDD to demonstrate finely granular, electron-dense deposits in the mesangial nodules and along the endothelial aspect of the glomerular basement membrane.²⁸ In cases of tubular involvement, the deposits are noted along the outer aspect of the membrane.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical Care

Treatment for LCDD should be aimed at reducing the clonal plasma cells responsible for the production of immunoglobulin light chains.

Treatment options for patients with LCDD include the following:

• Cytotoxic chemotherapy, such as melphalan/prednisone, chlorambucil, or azathioprine^{1, 9, 13, 24}
• • Intermediate-dose infusion regimens, including vincristine, doxorubicin, and dexamethasone (VAD) or vincristine, doxorubicin, and methylprednisolone (VAMP) may also be used. Newer therapies applicable to multiple myeloma such as lenolidomide and/or bortezomib may be considered, but data are limited.²⁹
• Autologous stem cell transplantation
• Kidney transplantation

Treatment for LCDD is variable. Although a few patients with renal disease with no evidence of myeloma are not treated, most receive chemotherapy as used for myeloma.²⁹ These patients show varying outcome (eg, one study showed a better outcome with vincristine-doxorubicin-dexamethasone/methylprednisolone therapy).

Studies demonstrating the role of autologous stem cell transplantation alone for patients with LCDD are very limited. Firkin et al reported a case of LCDD in which dialysis-dependent renal failure was reversed following autologous peripheral stem cell transplantation.¹⁴

Nonetheless, high-dose melphalan therapy with stem cell transplantation has been used in a small number of patients with LCDD, most of whom had concurrent myeloma. These studies demonstrate better outcome with minimal side effects.^{1, 13} 

A study by Royer et al included 11 patients, 10 of whom had multiple myeloma.¹³ Following high-dose chemotherapy with stem cell transplantation, complete hematologic response was achieved in 6 patients, and a partial response in 2 patients. In addition, renal, cardiac, and hepatic functions improved in 6 patients, and regression of light-chain deposits in cardiac, liver, and skin biopsies were observed. Monoclonal immunoglobulin levels decreased in 8 patients, with complete disappearance from urine and serum in 6 cases. No deaths related to treatment were observed.¹³ 

A similar experience was observed by Weichman et al who treated 6 cases of LCDD with high-dose melphalan and autologous stem cell transplantation.¹ However, no history of myeloma was noted. A complete hematologic response was achieved in 5 of 6 patients, and all were alive at a median follow-up of 12 months.¹ Moreover, the serum free light-chain levels normalized in all 6 patients. Again, there were no treatment-related deaths.

The above studies show that high-dose melphalan with subsequent autologous stem cell transplantation may be the treatment of choice for patients with LCDD regardless of their myeloma status. The hematologic responses were acceptable with regression of light-chain deposits and low treatment-related mortality rates.     

Kidney transplantation has been performed in small number of patients with LCDD. The disease recurs in the allograft in 80% of cases, and the outcome is poor due to recurrence of disease in the renal allograft or progression of the underlying plasma cell disorder.

In a study by Leung et al, 7 patients with LCDD who were treated with kidney transplantation were retrospectively reviewed.³⁰ All 7 had nephrotic-range proteinuria and were maintained on hemodialysis before transplantation. LCDD recurred in 5 of 7 patients. One patient died of progression of multiple myeloma without evidence of recurrence. One patient remained free of disease 13 years after the kidney transplantation.³⁰ The authors concluded that renal transplantation should not be considered as a treatment option unless measures have been taken to reduce light-chain production.

The potential role rituximab is questionable. A case was reported in which therapy with rituximab delayed the recurrence of LCDD in a patient with second renal allograft.³¹  

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

No standard treatment of LCDD is established. Several agents, such as high dose melphalan/prednisone, and autologous stem cell transplantation, have been tried experimentally in different small case series. As in AL-amyloidosis, larger, controlled trials are needed to define the best combination of chemotherapy and the support of stem cell rescue according to the clinical presentation and severity of renal failure. The optimal therapy or the length of treatment is unknown, but treatment is usually continued until clinical and pathologic responses are stable or improving.

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Resource Center Cancer: Biologic Therapies
Resource Center Multiple Myeloma
Specialty Site Hematology-Oncology

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Prognosis

• Patient and renal survival in patients with LCDD is variable, ranging from 1 month to 10 years. If untreated, ESRD occurs in 70% of cases. A study by Pozzi et al which included 63 patients demonstrated 52% patient and 40% renal survival rates for a 4-year period.³² Renal prognosis is affected by the patient's age and serum creatinine levels at presentation.
• Overall survival has been shown to be influenced by patient age, the presence of coexisting multiple myeloma or cast nephropathy, and any evidence of extrarenal light-chain deposition.   
• The natural or treated history of LCDD is difficult to determine as this disease is uncommon. 

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

Medical/Legal Pitfalls

• Failure to diagnose LCDD may lead to the inability to prevent or delay the progression of end-organ damage and/or allow for screening for transformation to a neoplastic process. Note: This statement should be cautiously interpreted because the disease does not present with common signs or symptoms, and the impact of therapy on the outcome is not well studied.

Related Medscape topic:
Resource Center Medical Malpractice and Legal Issues

ACKNOWLEDGMENTS

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor Dr Jaya Juturi to the development and writing of this article.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• References

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Article Last Updated: Jun 4, 2008