Light-Chain Deposition Disease 

Updated: Jan 15, 2017
Author: Swapna Boppana, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Light-chain deposition disease (LCDD) is the deposition of monoclonal light chains in multiple organs. It is a rare disease characterized by deposition of nonamyloid immunoglobulin light chains, and they do not stain with Congo red and do not exhibit a fibrillar structure when examined ultrastructurally.[1, 2, 3] It is categorized as a “monoclonal deposition disease” in the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues.[4, 56] LCDD was first described in 1976 in two patients with end-stage renal disease as granular deposits of free light chains in multiple organs, including the kidneys, that did not stain with Congo red.[5]

A single clone of plasma cells is responsible for overproduction of kappa chains and, very rarely, lambda chains.[6] A monoclonal population of plasma cells can be detected in the bone marrow, and an altered serum-free light chain ratio is present.[7] In 25% of patients, an abnormal serum free light chain ratio is noted, even without an abnormal finding with serum and or urine electrophoresis with immunofixation.[8]

The incidence of LCDD is unknown. The median age at diagnosis is 58 years, and it is more common in men than in women.[7] Approximately 50-60% of patients with LCDD have associated multiple myeloma and 17% have monoclonal gammopathy of unknown significance (MGUS) or no evidence of neoplastic plasma cell proliferation.[4]

LCDD can occur in any organ.[9] Kidneys are always involved, and LCDD can present as renal insufficiency, proteinuria, microscopic hematuria, and nephrotic syndrome. Albuminuria levels do not correlate with the presence of glomerulonephritis and can be present even without glomerulosclerosis.[10] Renal function declines rapidly as a rapidly progressive glomerulonephritis or acute tubulointerstitial nephritis.[4]

Extrarenal involvement is primarily noted at autopsy and is usually confined to the perivascular regions of the affected organs.

The approach for diagnosis with LCDD should be the same as for patients with plasma cell dyscrasias.[11] It should include a thorough history, physical examination, and laboratory and imaging studies (see Presentation and Workup). LCDD should be distinguished from Fanconi syndrome, myeloma cast nephropathy, cryoglobulinemia, and amyloidosis, all of which are also associated with monoclonal proteins.

LCDD is a rare disease, so no established guidelines exist and management remains controversial.[37] Treatment options include the following (see Treatment):

  • Autologous stem cell transplantation (ASCT)

  • Bortezomib

  • Immunomodulatory drugs

  • Renal transplantation

Pathophysiology

Renal light-chain deposition disease (LCDD) is characterized by the presence of: nodular sclerosing glomerulonephritis on light microscopy; diffuse linear staining in the glomerular and tubular basement membrane by a single light chain on immunofluorescence; and nonfibrillar, powdery, electron-dense deposits in the basements on electron microscopy.[12] Mesangial nodularity within the glomerulus occurs from the increased deposition of extracellular matrix proteins mixed with kappa light chains.[12]

The necessary criterion to make the diagnosis of LCDD requires that all tissues to be stained for kappa and light chains and the tissue must exhibit kappa fixation along the tubular basement membrane.[13, 14, 15] The tubular deposits are present predominantly along the loops of Henle, distal tubules, and proximal tubules.

Amyloid light-chain (AL)–amyloidosis consists predominantly of lambda light chains, whereas kappa light chains are predominantly involved in LCDD. Electron microscopy is helpful in distinguishing between these lesions.

Extrarenal involvement

Symptomatic extrarenal LCDD is rare.[16] The liver is the most frequent site involved.[8, 17] The deposits in the liver are usually confined to the sinusoids and basement membrane of biliary ducts, without associated parenchymal lesions. The degree of liver involvement does not correlate with the amount of light chains deposited.[17] Patients may develop cirrhosis and/or portal hypertension and may die from liver failure.[8]

The cardiac manifestations include restrictive cardiomyopathy, cardiomegaly, congestive heart failure, and arrhythmias.[18, 19, 20] Echocardiography and cardiac catheterization may reveal diastolic dysfunction and decreased myocardial compliance.[21]

Pulmonary LCDD is rare, and it usually damages the lung parenchyma. Involvement of the large airways has recently been reported.[22] Nodular and diffuse pulmonary interstitial diseases of the lungs have been described.[23, 24, 25]

LCDD can affect peripheral nerves, resulting in polyneuropathy.[26] Isolated LCDD restricted to the brain has been reported as well, wherein the periventricular foci of intracerebral vessels were overloaded with amorphous, eosinophilic material that stained for lambda light chains.[27] In general, the blood-brain barrier protects the central nervous system (CNS) from circulating, misfolded proteins, but cases of intracerebral amyloidoma have been reported.[28]

LCDD can also affect other sites, such as lymph nodes, skin, spleen, pancreas, bone marrow, thyroid gland, adrenal gland, and abdominal blood vessels.[7]

LCDD is associated with multiple myeloma is about 58% of cases.[4] LCDD could be present at diagnosis of a new plasma cell dyscrasia or could represent an extramedullary manifestation of multiple myeloma while relapsing after chemotherapy.[21] LCDD can also complicate other B-cell lymphomas, such as lymphoplasmacytic lymphoma, marginal-zone lymphoma, and chronic lymphocytic lymphoma.[29]

Epidemiology

Frequency

United States

The frequency of light-chain deposition disease (LCDD) is unknown. The disease is found in approximately 5% of patients with multiple myeloma at autopsy.

Mortality/Morbidity

The most common cause of mortality and morbidity in light-chain deposition disease (LCDD) is related to renal complications, including hypertension, nephrotic syndrome, and progression to end-stage renal disease (ESRD). 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.

 

Presentation

History

Patients are found to have light-chain deposition disease (LCDD) when they are evaluated for proteinuria or nephrotic syndrome by renal biopsy. The common 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, owing to a delay in the diagnosis.

Physical

Light-chain deposition disease (LCDD) patients may present with end organ damage, which chiefly manifests as hypertension, peripheral edema, neuropathy, or congestive heart failure. Approximately 50% of patients with LCDD present with nephrotic syndrome. However, in a quarter of patients, the proteinuria is less than 1 g/day as a result of tubulointerstitial involvement.

Causes

The specific etiology is unknown.

 

DDx

 

Workup

Laboratory Studies

The laboratory workup for light-chain deposition disease (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 the presence of a monoclonal protein

  • Repeated studies of serum and urine protein immunoelectrophoresis (PEL) with immunofixation (IFE), to demonstrate the presence of monoclonal protein

  • In a minority of patients, a monoclonal protein may never be found in either serum or urine

  • Quantitative serum assays for immunoglobulin free light chains: The recent introduction of this test has increased the sensitivity of laboratory tests to identify monoclonal gammopathies.[30, 31]

The most recent diagnostic screening recommendations are serum PEL with IFE and quantitative serum assays for free light chains.[32] It is also recommended that urine PEL and IFE should be included when screening for amyloid light-chain (AL)–amyloidosis or LCDD.[11, 30] When all three are combined, the sensitivity for LCDD is 83%, but decreases to 77.8% when urine PEL with IFE is omitted. Excluding the quantitative serum assays for free light chains also decreased the sensitivity for detection of LCDD.

Sometimes these tests can still miss the presence of a monoclonal protein, thus kidney biopsy is needed for adequate and timely diagnosis.[9, 33] Tissue should be sent for immunohistologic analysis for confirmation; it is noncongophilic in nature. Light-chain restriction analyses confirm the presence of monoclonal light or heavy chain.

Imaging Studies

Echocardiography and ultrasonography of abdomen should be performed. Nerve conduction studies, CT scanning, MRI, or positron emission tomography (PET) are performed as needed.[34]

Procedures

Biopsy procedures are as follows:

  • 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 and biopsy to rule out multiple myeloma

Histologic Findings

The electron microscopic changes characteristic of light-chain deposition disease (LCDD) demonstrate finely granular, electron-dense deposits in the mesangial nodules and along the endothelial aspect of the glomerular basement membrane.[14, 15, 33] In cases of tubular involvement, the deposits are noted along the outer aspect of the membrane.

 

Treatment

Medical Care

Treatment of light-chain deposition disease (LCDD) is indicated for patients who present with systemic involvement, renal dysfunction, and associated presence of multiple myeloma. The goal of treatment in these patients is to suppress the production of light chains and damage to other organs. Appropriate medical management must be provided for organ dysfunction as needed, such as the use of angiotensin-converting enzyme (ACE) inhibitors or dialysis.

Unlike in multiple myeloma, the plasma cell burden is quite low (< 5%) and the genetic abnormalities associated with adverse prognosis in multiple myeloma are absent. In patients with LCDD associated with multiple myeloma, the prognosis is quite poor and they should be treated per multiple myeloma guidelines.[35] In these patients, there is no evidence to support maintenance therapy except for an anecdotal report in 1 patient who received thalidomide maintenance following chemotherapy.[36] LCDD is a rare disease, hence there are no established guidelines and management remains controversial.[37]

Treatment options include the following[53] :

  • Autologous stem cell transplantation (ASCT)

  • Bortezomib

  • Immunomodulatory drugs

  • Renal transplantation

Autologous stem cell transplantation

Stem cell transplantation can produce durable responses in patients with LCDD.[37, 38, 39] Stem cells are mobilized using granulocyte colony-stimulating factor (G-CSF), and high-dose chemotherapy with melphalan is given. The dose of melphalan is adjusted to the renal function to decrease morbidity.

A long-term analysis of 6 patients with LCDD who underwent ASCT demonstrated that this is an effective therapy for patients with renal dysfunction due to LCDD.[37] Proteinuria was reduced by 92%, and the glomerular filtration rate improved by 95% in these patients. The authors also suggest if kidney dysfunction persists after ASCT, a hematological response may permit successful kidney transplantation with improved graft viability and decreased risk of recurrence. Another study of patients with LCDD treated with high-dose melphalan followed by ASCT also demonstrated that patients with renal dysfunction have improvement in renal function following ASCT.[40] Of the 5 evaluable patients with hematological response, one had complete response and four with partial response.

The use of high dose chemotherapy followed by ASCT is associated with toxicities such as mucositis, sepsis, bacteremia, and diarrhea. In general, LCDD patients are younger; thus, ASCT should be considered in these patients. However, associated comorbidities, presence of cardiac involvement, concomitant presence of multiple myeloma, and number of organs affected may predict for a worse outcome. Therefore, age and comorbidities should be considered prior to ASCT. Multiorgan failure following ASCT has been reported in patients with extrarenal disease.[37]

Bortezomib

In light-chain deposition disease (LCDD), monoclonal light chains interact with the receptors in mesangial cells and activate many pathways including the nuclear factor (NF)kB pathway. This results in increased cytokine production leading to cell proliferation and activation of genes responsible for collagen and tenascin production. These changes lead to changes in the mesangial matrix ,causing glomerulosclerosis.[9, 12] Bortezomib inhibits the NFkB pathway, decreases cytokine production, and decreases collagen production.[41, 42] The downstream cascade is interrupted by bortezomib preventing rapid progression of glomerulosclerosis and proteinuria and improving the renal function.[42, 43]

Bortezomib has been used in small series of patients with LCDD, including as induction therapy.[39, 44, 45] In one series, 3 patients were treated with bortezomib as induction therapy. This led to rapid hematologic response after a mean of 2 cycles based on decrease in serum free light-chain levels.[44] Another series reported the use of bortezomib with dexamethasone as induction therapy prior to autologous stem cell transplantation (ASCT) in 4 patients, which lead to rapid response with 50% of patients with complete hematologic response.[45] A Canadian group reported the use of bortezomib and dexamethasone as induction therapy in 2 patients prior to ASCT, and both achieved partial response after 3 cycles and organ response 6 months after ASCT.[38]

The Canadian group also reported the only randomized study of 6 patients with LCDD. Patients were randomized to either dexamethasone alone or bortezomib with dexamethasone prior to high-dose chemotherapy with melphalan followed by ASCT. After completion of induction therapy 4 of 6 patients achieved partial response based on the decrease in serum free light-chain ratio and 2 of 6 achieved stable disease and both were in dexamethasone alone group.

At day 100, the post-ASCT overall response rate was 100%; 4 patients achieved complete hematological response, 1 exhibited near-complete response, and 1 attained partial response. All patients derived clinical benefit, including those who achieved less than complete response. At 6 months post-ASCT, all 6 patients showed organ response manifested mainly by decreased proteinuria of greater than 50%. Patients receiving bortezomib and dexamethasone induction showed a median time of kidney response of 3 months versus 6 months for the group receiving only dexamethasone. All 6 patients are alive after a median follow up of 2 years and have remained dialysis free.[46]

Based on the limited available data, induction with bortezomib helps improve renal function. This may possibly lead to more high-dose chemotherapy followed by ASCT, enabling for a better outcome. With bortezomib-based therapy, hematologic responses are rapid and are normally accompanied by rapid and significant reduction of proteinuria and improvement of renal function. The measurement of serum free light chains was useful in the follow-up of patients with LCDD, and the reduction of involved light chains was associated with significant improvement of proteinuria. High dose chemotherapy followed with ASCT is a safe and well-tolerated treatment for LCDD, showing a good overall response rate.

Immunomodulatory agents

Thalidomide is an immunomodulatory drug that has been extensively studied in amyloid light-chain (AL)–amyloidosis and multiple myeloma. The use in LCDD has been limited. A report in one young patient in whom conventional chemotherapy failed demonstrated that thalidomide with dexamethasone was able to provide a complete hematological response after 8 months. The patient had a sustained hematological response with improvement in renal function that lasted 31 months.[47]

Another case was reported in a patient with liver involvement who was given lenalidomide with melphalan and prednisone. However, lenalidomide was discontinued as the patient unfortunately developed intrahepatic ischemic cholangitis.[48]  

In another case, melphalan and prednisolone (MP) therapy was started upon diagnosis and continued for 10 years with serial evaluations of renal histology revealing the resolution of nodular lesions, and the glomeruli became nearly normal.[55] The immunomodulatory agents are promising but their role needs to be further explored in prospective studies.

Renal transplantation

A few patients with LCDD with ESRD have undergone renal transplantation.[49]  Long-term benefits are seen, but allograft survival is significantly reduced in this patient population.[54] LCDD patients who have detectable light chains in urine or serum have worse outcomes, with early recurrences despite pretransplantation treatment.[50] Thus, transplantation should be reserved for select patients with a relatively slow course in whom light-chain production can be controlled by directed therapy.

Despite all careful consideration, recurrences develop and sometimes can be confused with acute rejection. A recent study with bortezomib in a single patient suggests that it can successfully reverse early recurrence of LCDD in the allograft.[51] Rituximab could also be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response.[52] The possibility of maintenance with either bortezomib, thalidomide, or rituximab needs to be further explored.

 

 

Follow-up

Prognosis

Median survival for patients with light-chain deposition disease (LCDD) is about 4 years. The largest series published so far has reported after a median follow-up of 27 months; 57% of patients developed uremia and 59% of patients died.[7] The prognostic factors are age, associated multiple myeloma, and extrarenal light-chain deposition.[4, 12] The presence of end-stage renal disease (ESRD) and need for dialysis did not change the outcome for these patients.

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.

 

Questions & Answers

Overview

What is light-chain deposition disease (LCDD)?

What is the pathophysiology of light-chain deposition disease (LCDD)?

What is the pathophysiology of extrarenal light-chain deposition disease (LCDD)?

What is the prevalence of light-chain deposition disease (LCDD)?

What is the morbidity and mortality associated with light-chain deposition disease (LCDD)?

Presentation

Which clinical history findings are characteristic of light-chain deposition disease (LCDD)?

Which physical findings are characteristic of light-chain deposition disease (LCDD)?

What causes light-chain deposition disease (LCDD)?

DDX

What are the differential diagnoses for Light-Chain Deposition Disease?

Workup

What is the role of lab tests in the workup of light-chain deposition disease (LCDD)?

What is the role of imaging studies in the workup of light-chain deposition disease (LCDD)?

What is the role of biopsy in the workup of light-chain deposition disease (LCDD)?

Which histologic findings are characteristic of light-chain deposition disease (LCDD)?

Treatment

How is light-chain deposition disease (LCDD) treated?

What is the role of autologous stem cell transplantation in the treatment of light-chain deposition disease (LCDD)?

What is the role of bortezomib in the treatment of light-chain deposition disease (LCDD)?

What is the role of immunomodulatory drugs in the treatment of light-chain deposition disease (LCDD)?

What is the role of renal transplantation in the treatment of light-chain deposition disease (LCDD)?

Follow-up

What is the prognosis of light-chain deposition disease (LCDD)?