AUTHOR INFORMATION	Section 1 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Author: Malvinder S Parmar, MB, MS, FRCPC, FACP, FASN, Assistant Professor (VPT), Faculty of Medicine, University of Ottawa, Associate Professor, Northern Ontario School of Medicine, Department of Internal Medicine, Timmins and District Hospital, Ontario

Malvinder S Parmar, MB, MS, FRCPC, FACP, FASN, is a member of the following medical societies: American College of Physicians, American Society of Nephrology, Canadian Medical Association, International Society of Nephrology, Ontario Medical Association, and Royal College of Physicians and Surgeons of Canada

Editor(s): Frank C Brosius III, MD, Nephrology Program Director, Professor of Internal Medicine and Physiology, Department of Internal Medicine, Division of Nephrology, University of Michigan School of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Christie Thomas, MD, FACP, FAHA, FASN, Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Hospitals and Clinics; Rebecca J Schmidt, DO, FACP, FASN, Clinical Associate Professor of Medicine, West Virginia School of Osteopathic Medicine; Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine; and Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Chief, Section of Nephrology, Tulane University School of Medicine; Professor, Renal-Hypertension Section, Department of Medicine, Tulane University Medical Center and Veterans Affairs Medical Center

Disclosure

	INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Thomas Alexander McBean died on New Year's Day in 1846. The cause of death was certified as "atrophy from albuminuria." Thomas Watson, MD, a general practitioner, had observed some unusual properties in this patient's urine and described them to Henry Bence Jones, MD, in his letter dated Saturday, November 1, 1845, as follows:

Dear Dr. Jones,

...The tube contains urine of very high specific gravity. When boiled, it becomes slightly opaque. On addition of nitric acid, it effervesces, assumes a reddish hue, and becomes quite clear, but as it cools, assumes the consistency and appearance which you see. Heat reliquifies it. What is it?

The clinical features were summarized as follows:

When I saw the patient, there was excessive emaciation, yellowish skin, clear conjunctivae, lips dry, tongue fissured, moist, furred at the back, pulse 85, small, skin moist, bowels - tendency to diarrhoea, motions reported not unhealthy, urine not passed in large quantities, no urgency - no frequency, pinkish urates deposited, much mucous rales in the chest, over-strong pulsation of heart, complained of pain in the left shoulder and side, was obliged to be moved most gently in bed on account of the pain.

At autopsy, the remarkable feature was the "softness of bones," which gave rise to the original name to the condition, mollities ossium.

Since the initial report, the term Bence Jones protein has been used to designate a urinary protein that leaves solution at approximately 56°C under certain conditions of pH and ionic strength and returns to the solution upon further heating to 100°C. The Bence Jones protein represents a homogeneous population of immunoglobulin light chains of either kappa type or lambda type and is the product of a presumed single clone of plasma cells. The presence of light-chain proteins in the urine is associated with a number of systemic diseases (see Causes).

Smithline et al first used the term light-chain nephropathy in 1976 to describe a case of renal tubular dysfunction with light-chain proteinuria. Recently, the term has been associated with various glomerular abnormalities that are caused by the deposition of these monoclonal immunoglobulins (or their heavy-chain [HC] or light-chain [LC] subunits) and are broadly classified into 2 categories depending on the pattern of deposition, as follows:

• Organized deposits
  • Fibrillar (amyloidosis)

  • Microtubular (cryoglobulinemia, immunotactoid glomerulonephritis)

• Nonorganized, granular deposits
  • Monoclonal immunoglobulin deposition disease (MIDD)

  • Light-chain, heavy-chain, and light- and heavy-chain deposition disease

Pathophysiology:

Normal (renal) handling of light-chain proteins

Light chains (molecular weight 22,000 d) are polypeptides synthesized by plasma cells and assembled with heavy chains to form the various classes of immunoglobulins, eg, immunoglobulin G (IgG), immunoglobulin M (IgM), and immunoglobulin A (IgA). Plasma cells normally produce a slight excess of light chains that are either excreted or catabolized by the kidney.

Light chains are divided into 2 major classes based on the amino acid sequence in the constant portion of the polypeptide chain and are designated as kappa and lambda. These are further divided into at least 10 subtypes (4 kappa and 6 lambda) based on the amino acid sequence in the variable region of the polypeptide chain. Individual immunoglobulins have either kappa or lambda light chains, but not both.

Kappa light chains usually exist as monomers (22,000 d) and are therefore small enough to be filtered through the glomerulus, but they may exist as dimers. Lambda light chains usually exist as dimers (44,000 d) and, therefore, are less likely to be filtered and appear in urine. At times, light chains of either kappa or lambda type may form tetramers (88,000 d), which are not filtered, and a patient may have light-chain proteinemia without light-chain proteinuria.

The kidney is the major site of metabolism of light-chain proteins. The filtered light-chain proteins, reabsorbed by the proximal tubular cells via the tandem megalin/cubilin receptors, are catabolized by lysosomal enzymes. This process is exceedingly efficient, and only a minute amount of light-chain protein normally appears in the urine. Metabolism (catabolism) of these filtered light-chain proteins depends on normal proximal tubular cell function, and damage to these cells can result in increased excretion of light-chain proteins in the urine. Hence, light-chain proteins appear in urine in high concentration either when the production of light-chain proteins is markedly increased or when the ability of the proximal tubules to reabsorb all the filtered protein is exceeded.

Glomerulopathic light-chains (G-LC) interact with mesangial cells and alter the mesangial homeostasis in 2 different ways, depending on whether G-LC is from a patient with LCCDD or amyloidosis. In contrast, the tubulopathic light chains (T-LC) from patients with myeloma cast nephropathy do not significantly interact with mesangial cells and do not alter mesangial homeostasis. Some of these light chains are toxic to proximal tubule cells and induce inflammatory/proinflammatory cytokines that may contribute to kidney disease in myeloma.

Light-chain proteins may manifest in the urine because of (1) asymptomatic light-chain proteinuria, (2) proximal tubular dysfunction (ie, Fanconi syndrome), (3) chronic or acute renal failure, (4), LCDD (ie, nodular glomerulosclerosis, or, rarely, glomerulonephritis), (5) cast nephropathy, or (6) amyloidosis.

The isoelectric point (pI) of the light chain may be an important determinant of its potential for inducing renal damage. Proteins with a relatively high pI (>5.8-6) appear to be more likely to be associated with renal failure. These light chains have a cationic charge at acidic urine pH in the distal nephron. This allows them to interact with anionic Tamm-Horsfall mucoprotein, thereby forming obstructing casts. However, some investigators have been unable to confirm the correlation between nephrotoxicity and pI of the light-chain proteins.

Fanconi syndrome (proximal tubular dysfunction)

Fanconi syndrome is a generalized dysfunction of the proximal tubule resulting in variable degrees of phosphate, glucose, amino acid, and bicarbonate wasting by the proximal tubule. This may occur as a hereditary disorder (in children) or as an acquired form. Acquired forms in adults are usually associated with paraproteinemias. Light-chain proteins are catabolized in the proximal tubules, and their clearance varies inversely with the clearance of creatinine. Increased concentration of light chains exerts a toxic effect on renal tubular function, resulting in Fanconi syndrome (proximal tubular dysfunction), distal renal tubular acidosis, or nephrogenic diabetes insipidus, depending on the site of action.

Light chain deposition disease

LCDD is a systemic disease caused by the overproduction and extracellular deposition of monoclonal light chains.

Deposition does not mean pathogenicity. Deposition of light-chains similar to LCDD by IF but with no or only scanty granular electron dense deposits in the tubular basement membrane with no glomerular lesions or tubular basement membrane thickening has been described by Lin and Gallo. Hence, the IF staining of LC alone should not be considered a sufficient criteria for diagnosis of MIDD that is associated with local fibrosis. In approximately 80% of cases, these deposits are composed of kappa, rather than lambda, light chains. The deposits are granular and do not form fibrils or beta-pleated sheets and are negative for Congo red stain. These deposits are on the constant region of the immunoglobulin light chain, in contrast to the deposits associated with amyloidosis.

The pathogenesis of glomerulosclerosis in LCDD is not entirely clear, but pathogenic Ig chains stimulate mesangial cells to secrete extracellular matrix [ECM] components through growth factors, especially transforming growth factor-beta, that act as an autocoid and promote cells to produce matrix proteins, such as type IV collagen, laminin, fibronectin, and tenascin.

Myeloma kidney (cast nephropathy)

More than 50% of patients with multiple myeloma die from renal failure, and a large number of these deaths are erroneously attributed to so-called myeloma kidney. However, myeloma kidney is only one of the several causes of renal dysfunction in patients with multiple myeloma, in which specifically proteinaceous casts are observed obstructing the distal tubules and collecting ducts.

Factors that might contribute to myeloma cast nephropathy include (1) the direct toxicity of Bence Jones proteins to tubular cells, (2) protein complex formation in the distal nephron, (3) tubular fluid pH, (4) a reduction in renal plasma flow and glomerular filtration rate (ie, decreased urine flow), and (5) systemic electrolyte abnormalities (eg, hypercalcemia and dehydration).

Amyloidosis

Adams probably recognized the association of amyloidosis and multiple myeloma in 1872, but Magnus-Levy suggested a relationship between Bence Jones proteinuria (BJP) and amyloidosis in 1931. In 1971, Glenner et al demonstrated that amyloid fibrils from a patient with primary amyloidosis had an amino acid sequence almost identical to the variable portion of monoclonal light chains (ie, Bence Jones proteins) and that amyloid fibrils could be created from Bence Jones proteins, establishing a definite link between immunoglobulin light chains and one type of amyloid.

Amyloid is not a single substance, but a family of complex glycoproteins of variable composition. Amyloids have a common characteristic ultrastructure (nonbranching fibrils 7.5-10 nm wide and of indefinite length) and tinctorial properties (green birefringence when stained with Congo red). These characteristics are related to the beta-pleated sheet configuration that all types of amyloid are found to have when examined using x-ray diffraction. Two major types of amyloid fibrils have been identified.

The first is AA amyloid. The major component of AA amyloid is a protein consisting of 76 amino acids with a molecular weight of 8500 d that is unrelated to immunoglobulins. This type is found in patients with secondary amyloidosis associated with rheumatoid arthritis, syphilis, chronic osteomyelitis, and familial Mediterranean fever.

The second is AL amyloid. Immunoglobulin light chains are the major constituent of AL amyloid, which is found in patients with primary amyloidosis and multiple myeloma. Of patients with multiple myeloma, 6-24% develop amyloidosis. Conversely, among patients presenting with primary (AL) amyloidosis, a substantial proportion have, or eventually develop, a plasma cell dyscrasia with plasmacytosis in the bone marrow, immunoglobulin light chains in the serum, and BJP.

The mechanism of amyloid fibril formation remains unknown. Studies on animal models and in vitro studies of secondary (AA) amyloidosis suggest that in response to chronic injury, monocytes are activated and release interleukin-1, which acts on the liver to induce synthesis of a precursor protein designated as serum amyloid (SAA). SAA is then degraded by macrophages under the influence of certain enhancing factors to form amyloid fibrils. Although no such model exists for AL amyloidosis, it appears that the final event, the production of the fibrils by macrophages, is similar for all types of amyloid.

Frequency:

• In the US: The occurrence of light-chain proteinuria (ie, BJP) depends on the underlying condition.
  • The incidence of monoclonal gammopathies increases with age. They occur in 1-5% of persons older than 65 years.

  • Overall, BJP occurs in 47-70% of persons with multiple myeloma, with the specific rate depending on the type of myeloma. With IgG myeloma, the rate is 60%. With IgA myeloma, the rate is 71%. With immunoglobulin D (IgD) myeloma, the rate is 100%.

  • Of patients with Waldenström macroglobulinemia, 30-40% have BJP.

  • Of patients with primary amyloidosis, 92% have BJP.

Mortality/Morbidity: Overall, the prognosis depends on the type and extent of the underlying condition. Renal failure is much more prevalent in patients with light-chain proteinuria, and the severity of the renal failure correlates with the light-chain protein excretion rate. Acute renal failure is observed less frequently (8-30%), while chronic renal failure is quite common (30-60%).

• Benign monoclonal gammopathy: Clinical renal disease is uncommon in persons with true benign monoclonal gammopathy. Only 1-2% have mild renal insufficiency, and some have mild proteinuria or hematuria.

• Light-chain deposition disease: Prognosis for patients with LCDD is generally poor, and death is often attributed to cardiac disease, heart failure, or infectious complications. The survival rate is 90% at 1 year and 70 % at 5 years, with renal survival in 67% and 37% at 1 and 5 years, respectively, after chemotherapy (ie, with melphalan and prednisone).

• Multiple myeloma: Infections and renal failure are the major causes of death in patients with multiple myeloma. Renal failure represents the most important factor influencing survival in patients with multiple myeloma. Despite aggressive therapy, patients with renal failure and myeloma have a considerably worse prognosis compared to those with myeloma who do not have renal insufficiency. The prevalence rates for renal failure are also related to the type of myeloma, ie, 14% of patients with IgG myeloma, 33% of those with IgA myeloma, and 60% of individuals with IgD myeloma have renal failure.
  
  
• Amyloidosis: The prognosis for patients with AL amyloidosis is poor, with a median survival of less than 2 years in most series. In a review of patients treated with melphalan and prednisone, the overall median survival was 89.4 months (78% 5-y survival rate) in responders versus 14.7 months (7% 5-y survival rate) in nonresponders.

Race: No racial predilection is recognized for this condition.

Sex: Light chain–associated renal syndromes are common in men.

• BJP is common in men.

• In one study, the incidence of light-chain nephropathy was 10 times higher in men compared to women.

• In AL amyloidosis, men are affected twice as often as women.

Age: BJP usually manifests in the fifth to seventh decade of life (age 40-66 y).

• AL amyloidosis occurs in patients older than 50 years (median age 59-63 y).

• Multiple myeloma reaches a peak in the eighth decade in men, and fewer than 1% of cases are diagnosed in patients younger than 40 years.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History: Patients with light-chain nephropathy may present with symptoms of underlying systemic disease and/or with symptoms of associated renal syndrome(s).

• Symptoms of underlying systemic disease

• Weakness or lethargy

• Weight loss, anorexia

• Bone pain: This occurs in 80% of patients with myeloma.

• Symptoms of peripheral neuropathy: These include numbness and burning pain in the lower extremities.

• Symptoms of compression fracture

• Symptoms secondary to associated renal syndromes

• Symptoms of acute (5-30%) or chronic (30-60%) renal failure: These may include peripheral edema and dyspnea.

• Symptoms of Fanconi syndrome (proximal tubular dysfunction): Fanconi syndrome occurs in up to 30% of patients with light-chain proteinuria. Varying degrees of glucosuria, aminoaciduria, phosphaturia, lysozymuria, and proximal tubular acidosis can occur in these patients. Fanconi syndrome is associated almost exclusively with kappa light-chain proteinuria, with the exception of 2 patients reported with lambda light-chain proteinuria.

• Asymptomatic: Normal renal function is observed in 10-40% of patients with light-chain proteinuria. Many patients with multiple myeloma have no demonstrable renal dysfunction despite persistent light-chain proteinuria. The amount, type, or duration of light-chain proteinuria does not correlate with the level of renal dysfunction.

• Nephrotic syndrome: Characterized by edema, hypoalbuminemia, and nephrotic range proteinuria (>3 g of urine protein per d), this may occur in 30% of patients.

• Polyuria and polydipsia

• History of or symptoms related to recurrent infections

Physical: Patients may have physical signs of underlying systemic illness and/or associated renal syndromes.

• Pallor

• Cachexia

• Dehydration

• Hypertension

• Edema

Causes: The following diseases are associated with light-chain proteinuria.

• Frequent associations

• Multiple myeloma (47-70%): The frequency of light-chain proteinuria depends on the type of myeloma.
  • IgG myeloma - Occurs in 60% (kappa light chain)

  • IgA myeloma - Occurs in 71% (kappa light chain)

  • IgD myeloma - Occurs in 100% (lambda light chain)

• Waldenström macroglobulinemia (30-40%): This is usually with IgM paraproteins. IgM is a pentamer and leads to hyperviscosity syndrome.

• Amyloidosis (92%): This is usually the lambda type.

• Less frequent associations

• Lymphoma: The associated type is malignant lymphoma.

• Leukemia: Types include chronic lymphocytic leukemia and plasma cell leukemia.

• Rare associations

• Nonreticular neoplasms: These may include angioimmunoblastic lymphadenopathy, adenocarcinoma of the pancreas, and medullary carcinoma of thyroid.

• Light-chain deposition disease

• Idiopathic BJP: This is the least common cause of light-chain proteinuria.

• Benign monoclonal gammopathy of unknown significance: A few of these patients may have detectable light-chain proteinuria, but the amount of protein is usually negligible.

• Drug-induced light-chain proteinuria: Rifampin is the implicated drug.

	DIFFERENTIALS	Section 4 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Amyloidosis, AA (Inflammatory)
Amyloidosis, Beta2M (Dialysis-Related)
Amyloidosis, Familial Renal
Amyloidosis, Immunoglobulin-Related
Diabetic Nephropathy
Light-Chain Deposition Disease
Multiple Myeloma
Waldenstrom Hypergammaglobulinemia