Light Chain-Associated Kidney Disease

Practice Essentials

Light chains (molecular weight 22,000 daltons) are polypeptides that are synthesized by plasma cells and form part of immunoglobulins (see the image below). Plasma cells normally produce a slight excess of light chains that are either excreted or catabolized by the kidney, and only a minute amount of light-chain protein normally appears in the urine. 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 diminished.

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Schematic representation of an immunoglobulin molecule

The most characteristic histologic lesion of light chain deposition disease (LCDD) is nodular glomerulosclerosis, which must be distinguished from diabetic glomerulosclerosis by using electron microscopy.^[1] See the image below.

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Light chain–associated renal disorders. Light microscopy (hematoxylin and eosin stain at 25X power) showing nodular glomerulosclerosis (arrow) and thi....

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 Etiology).

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

Organized deposits include the following:

• Fibrillar (amyloidosis)
• Microtubular (cryoglobulinemia, immunotactoid glomerulonephritis)

Nonorganized, granular deposits are found in monoclonal immunoglobulin deposition disease (MIDD), which has the following forms:

• LCDD
• Heavy-chain deposition disease
• Light- and heavy-chain deposition disease

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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, for example, 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 (44,000 d), which are less likely to be filtered and appear in urine. Lambda light chains usually exist as dimers. At times, light chains of either the kappa or lambda type may form tetramers (88,000 d), which are not filtered; this can result in 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 result from light chain deposition disease (LCDD) 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. However, some of these light chains are toxic to proximal tubule cells and induce inflammatory/proinflammatory cytokines that may contribute to kidney disease in myeloma.

Increased concentration of light chains may exert a toxic effect on distal renal tubular function. This can result in distal renal tubular acidosis or arginine vasopressin resistance (formerly known as nephrogenic diabetes insipidus).

Light-chain proteins may manifest in the urine in otherwise asymptomatic patients, or because of the following:

• Proximal tubular dysfunction (ie, Fanconi syndrome)
• Chronic kidney disease or acute kidney injury
• LCDD (ie, nodular glomerulosclerosis or, rarely, glomerulonephritis)
• Cast nephropathy
• Amyloidosis

The isoelectric point (pI) of the light chain may be an important determinant of its potential for damaging the kidney. Proteins with a relatively high pI (> 5.8-6) appear to be more likely to be associated with kidney 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 monoclonal gammopathies, such as LCDD.^[3]

Light chain deposition disease

LCDD is a systemic disease caused by the overproduction and extracellular deposition of monoclonal light chains.^[4]  Note that deposition does not necessarily mean pathogenicity. Cases have been described in which immunofluorescence (IF) microscopy shows deposition of light-chains similar to LCDD, but with no or only scanty granular electron-dense deposits in the tubular basement membrane, and with no glomerular lesions or tubular basement membrane thickening. Hence, IF staining of light chains alone should not be considered a sufficient criterion 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 and are granular; and do not form fibrils or beta-pleated sheets and are negative for Congo red stain, thioflavine T, or serum amyloid protein (SAP). In LCDD, the constant region of the immunoglobulin light chain is deposited; in contrast, in light chain (AL) amyloidosis, the fibrils are derived from the variable region of the light chains.^[5]

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

Myeloma kidney (cast nephropathy)

Approximately 25% of patients with multiple myeloma die from kidney failure,^[6] and a large number of these deaths are erroneously attributed to so-called myeloma kidney. In this condition, which is also known as myeloma cast nephropathy, proteinaceous casts are observed obstructing the distal tubules and collecting ducts. However, myeloma kidney is only one of the several causes of kidney dysfunction in patients with multiple myeloma.

Factors that might contribute to myeloma cast nephropathy include the following:

• The direct toxicity of the intact light chains to tubular cells (compared with deposition of light chain fragments in light chain deposition disease or amyloidosis)
• Protein complex formation in the distal nephron
• Tubular fluid pH
• A reduction in renal plasma flow and glomerular filtration rate (ie, decreased urine flow)
• Systemic electrolyte abnormalities (eg, hypercalcemia, hyperuricemia, hyperviscosity and dehydration)

Concomitant use of any of the following may precipitate acute kidney injury:

• Radiocontrast agents
• Nonsteroidal anti-inflammatory drugs
• Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers

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.^[7]

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.^[8]

Amyloid is not a single substance, but a family of complex glycoproteins of variable composition that undergo transformation (misfolding) to form beta-pleated fibrils. 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 and intense yellow-green fluorescence with thioflavine T) and bind to serum amyloid P (SAP). Several forms of amyloidosis are recognized, depending on nature of the precursor protein.

AL amyloid

Immunoglobulin light chains are the major constituent of these proteins, found in patients with primary (AL) amyloidosis and multiple myeloma. Of patients with multiple myeloma, 6-24% develop amyloidosis. Conversely, among patients presenting with 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 Bence Jones proteins.

AA amyloid (SAA)

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 chronic infections or inflammatory conditions, such as rheumatoid arthritis, syphilis, and chronic osteomyelitis.

Transthyretin (TTR; prealbumin)

This is wild-type or unmutated transthyretin in senile amyloidosis and a mutated form in familial amyloidosis.

Beta-2 microglobulin in dialysis-related amyloidosis

The factors that determine whether deposition of a given monoclonal light chain is fibrillar or granular are unclear and appear to be dependent on the biochemical properties of light chains and whether they are intact or in fragments. The light chains have been shown to self-associate to form high-molecular-weight aggregates that deposit in the tissues with or without fibril formation. Net charge of the protein may be an important determinant of amyloidogenic potential.^[9]

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, called cofactors, like serum amyloid P component (SAP), glycosaminoglycans, and certain apolipoproteins (E and J), and it is unclear whether these cofactors deposit during fibrillogenesis or after a fibrillogenic event.

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Etiology

Diseases frequently associated with light-chain proteinuria include mutiple myeloma, Waldenström macroglobulinemia, and amyloidosis.

In multiple myeloma, the frequency of light-chain proteinuria depends on the type of myeloma, as follows:

• IgG myeloma - Occurs in 60% (kappa light chain)
• IgA myeloma - Occurs in 71% (kappa light chain)
• IgD myeloma - Occurs in 100% (lambda light chain)

In 15% of multiple myeloma cases the clonal plasma cells are unable to produce heavy chains and instead exclusively produce light chains. Light-chain multiple myeloma has a more aggressive course and poorer prognosis than other types of multiple myeloma.^[10]

Light-chain proteinuria occurs in 30-40% of Waldenström macroglobulinemia cases, and usually comprises IgM paraproteins. IgM is a pentamer and leads to hyperviscosity syndrome. Amyloidosis (92%) is usually the lambda type.

Less frequent associations incluce malignant lymphoma, chronic lymphocytic leukemia and plasma cell leukemia. Rarer associations include nonreticular neoplasms such as angioimmunoblastic lymphadenopathy, pancreatic adenocarcinoma, and medullary thyroid carcinoma; light-chain deposition disease; and idiopathic Bence Jones proteinuria (the least common cause of light-chain proteinuria). In benign monoclonal gammopathy of unknown significance patients may have detectable light-chain proteinuria, but the amount of protein is usually negligible. Rifampin has been implicated in drug-induced light-chain proteinuria.

Light chains comprise most of the monoclonal immunoglobulin deposits in the kidney in monoclonal gammopathy of renal significance (MGRS). MGRS is defined as a B-cell or plasma cell clonal lymphoproliferation with one or more kidney lesions related to the produced monoclonal immunoglobulin, and in which the underlying clone does not cause tumor complications or meet any current hematologic criteria for specific therapy.^[11]

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Epidemiology

The occurrence of light-chain proteinuria depends on the underlying condition. No racial predilection is recognized for this condition. Light chain–associated renal syndromes are more common in men. In one study, the incidence of light-chain nephropathy was 10 times higher in men compared to women. The incidence of monoclonal gammopathies increases with age; they occur in 1-5% of persons older than 65 years.

Overall, Bence Jones proteinuria 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%. Onset of multiple myeloma peaks in the eighth decade in men, and fewer than 1% of cases are diagnosed in patients younger than 40 years.

Bence Jones proteinuria is more common in men and usually manifests in the fifth to seventh decade of life (age 40-66 y). Of patients with Waldenström macroglobulinemia, 30-40% have Bence Jones proteinuria.

Of patients with primary amyloidosis, 92% have BJP. Men are affected twice as often as women. AL amyloidosis occurs in patients older than 50 years (median age 59-63 y).

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Prognosis

Overall, the prognosis depends on the type and extent of the underlying condition. Kidney failure is much more prevalent in patients with light-chain proteinuria, and the severity of the failure correlates with the light-chain protein excretion rate. Acute kidney injury is observed less frequently (8-30%), while chronic kidney disease is quite common (30-60%). Kidney insufficiency may be indolent, chronic and progressive, or rapidly progressive.

Benign monoclonal gammopathy

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

Light-chain deposition disease

The 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

Acute kidney injury from light-chain cast nephropathy is a major complication of multiple myeloma. It is most often seen at initial diagnosis but may also develop at relapse. Of the four myeloma-defining events (hypercalcemia, kidney impairment, anemia,bone lytic lesions), kidney impairment has the greatest impact on survival, especially during the first 6 months. Although the advent of bortezomib and other novel agents has reduced mortality, patients with myeloma who have kidney impairment have a considerably worse prognosis than htose who retain normal kidney function.^[12]  

The degree of kidney impairment has a dramatic effect on the duration of survival, as follows:

• With a serum creatinine level of less than 120 µmol/L (1.4 mg/dL), median survival is 44 months
• With a serum creatinine level of 120-180 µmol/L (1.4-2 mg/dL), median survival is 18 months
• With a serum creatinine level greater than 180 µmol/L (>2 mg/dL), median survival is 4.3 months

The frequency of kidney failure varies with the type of myeloma. It occurs in 14% of patients with IgG myeloma, 33% of those with IgA myeloma, and 60% of individuals with IgD myeloma.

​Amyloidosis

The prognosis for patients with AL amyloidosis has improved markedly in recent decades, with survival of 15–20 years in approximately 30% of patients treated with high-dose melphalan and autologous stem cell transplantation. Staron et al reported that in patients with  AL amyloidosis, kidney failure accounted for 4% of deaths in the first 6 months after diagnosis and 18% of deaths beyond 5 years.^[13]

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Patient Education

Instruct patients to maintain adequate hydration, with a daily oral fluid intake of 2-3 liters, unless fluid restriction is needed because of advanced kidney failure.

Warn patients to avoid anti-inflammatory agents because these aggravate kidney dysfunction and may precipitate acute kidney injury.

Educate patients about the risk of contrast agents that may precipitate kidney failure. They should question the necessity of a contrast imaging study and request alternative studies, if available.

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History

Patients with light-chain nephropathy may present with symptoms of underlying systemic disease and/or with symptoms of associated renal syndrome(s). Alternatively, these patients may be asymptomatic. Normal kidney function is observed in 10-40% of patients with light-chain proteinuria. Many patients with multiple myeloma have no demonstrable kidney dysfunction despite persistent light-chain proteinuria. The amount, type, or duration of light-chain proteinuria does not correlate with the level of kidney dysfunction.

Symptoms of underlying systemic disease include the following:

• Weakness or lethargy
• Weight loss, anorexia
• Bone pain occurs in 80% of patients with myeloma
• Symptoms of peripheral neuropathy (eg, numbness and burning pain in the lower extremities)
• Symptoms of compression fracture
• Recurrent infections

Symptoms of acute kidney injury (5-30%) or chronic kidney disease (30-60%) may include peripheral edema and dyspnea.

Nephrotic syndrome is characterized clinically by edema, fatigue, and loss of appetite. This may occur in 30% of patients.

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Physical Examination

Patients may have physical signs of underlying systemic illness and/or associated renal syndromes, such as the following:

• Pallor
• Cachexia
• Dehydration
• Hypertension
• Edema

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Laboratory Studies

Urinalysis

Urinalysis results may indicate low-grade proteinuria. Nephrotic-range proteinuria may be present in patients with AL amyloidosis.

A discrepancy between the results of a urine dipstick test for protein and the findings from a test for 24-hour urine protein excretion should suggest the possibility of light-chain proteinuria. Light-chain proteins in the urine cannot be detected using Albustix or other dipstick methods.

The Putnam heat test or the sulfosalicylic acid (SSA) test (with Exton reagent) may detect urinary light-chain proteins, but both tests are insensitive. The Putnam heat test can help detect urinary light chains only when the concentration exceeds 150 mg/dL. False-negative results are common with the SSA test if the specific gravity of urine is less than 1.01.

If a patient has a negative result from the Albustix test (which detects albumin) and a positive result from the SSA test, consider the possibility of light-chain proteinuria.

Glucosuria may be observed in the absence of hyperglycemia.

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.

Urine immunoelectrophoresis

Light-chain proteins are best detected and identified using immunoelectrophoresis with monospecific antikappa and antilambda sera.

Blood studies

Results may be as follows.

Complete blood cell count

Anemia may be present in patients with multiple myeloma.

Serum electrolytes and serum bicarbonate with anion gap calculation

Because of the cationic charge of paraproteins, the level of this serum chloride is slightly elevated and the anion gap (see the Anion Gap calculator) is lower than normal.

Peripheral smear

Rouleaux formation is observed in patients with multiple myeloma and Waldenström macroglobulinemia.

Serum calcium

Hypercalcemia may be present in patients with multiple myeloma.

Serum protein electrophoresis and immunoelectrophoresis

These can be used to evaluate and quantitate the abnormal monoclonal spike.

Serum free-light chain assay

Free light-chain (FLC) assays have proved sensitive and specific for various light chain–associated disorders. In 110 patients with amyloidosis, the FLC kappa/lambda ratio was positive in 91% of patients, compared with 69% positive results with serum immunofixation (IFE) and 83% positive results with urine IFE.^[14] The combination of serum IFE and serum FLC detected an abnormal result in 99% of patients. Serum FLC assay is mainly helpful in monitoring response to therapy.^[15] In some patients with negative serum and urine electrophoresis for monoclonal protein, serum FLC was helpful in establishing diagnosis.^[16]

 Most cases of myeloma cast nephropathy occur in patients with serum FLCs above 100 mg/dL, and FLCs less than 70 mg/dL are rarely observed.^[17]

Serum electrolytes, including serum bicarbonate

Patients with tubular dysfunction may present with low or normal anion gap metabolic acidosis.

Serum albumin

Hypoalbuminemia and a reversal of the albumin-globulin ratio may be present.

Erythrocyte sedimentation rate

This is often significantly elevated in patients with myeloma.

Liver function studies

A moderate degree of liver dysfunction may be observed because of the deposition of light chains in the liver or other organs.

Serum creatinine 

An unusual case of light-chain proximal tubulopathy (LCPT) without any usual sign of tubular cell dysfunction apart from mild proteinuria, but with a complete abolishment of tubular secretion of creatinine, has been reported.^[18]  

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Imaging Studies

Renal ultrasound images can help assess kidney echogenicity and kidney size in patients presenting with kidney failure. Findings can also help to rule out renal calcification or stones. One third of the patients may have enlarged kidneys.

Skeletal surveys may show lytic bone lesions, osteoporosis, or compression fracture(s) in patients with possible multiple myeloma.

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Procedures

Findings from bone marrow aspiration and biopsy can be used to assess plasma cell infiltration.

Kidney biopsy is not mandatory, but it is useful when causes of kidney failure other than myeloma are under consideration.

When AL amyloidosis is suggested, consider performing a biopsy on the affected tissue. The diagnostic yield of various tissue biopsies is as follows:

• Kidney or liver biopsy - Greater than 90%
• Abdominal fat pad biopsy - 85%
• Rectal biopsy - 50-80%
• Gingival biopsy - 60%
• Skin biopsy - 58%

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Histologic Findings

Light chain–induced tubular dysfunction (Fanconi syndrome)

Needlelike crystals may be seen in renal tubular epithelial cells of some patients with light-chain proteinuria and Fanconi syndrome.

Classic myeloma kidney (cast nephropathy)

This condition is characterized by eosinophilic, dense, homogeneous casts that are often fractured or laminated and are partially surrounded by multinucleated foreign body–type giant cells. Congo red–positive casts have been reported in a few cases. Intratubular light chains apparently may undergo alteration in situ, resulting in amyloid formation.

Light-chain deposition disease

The most characteristic histologic lesion of LCDD is nodular glomerulosclerosis (see the first image below) that is virtually indistinguishable from diabetic glomerulosclerosis when using light microscopy. Routine immunofluorescence findings are negative because the antibodies used to identify the immunoglobulins are directed at the heavy chains of immunoglobulins. Therefore, as the name suggests, special stains for light chains must be used to identify this (see the second image depicted below) using electron microscopy.^[19]

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Light chain–associated renal disorders. Light microscopy (hematoxylin and eosin stain at 25X power) showing nodular glomerulosclerosis (arrow) and thi....

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Light chain–associated renal disorders. Immunofluorescence (25X power) showing deposits of monotypic light chain along the basement membrane. Courtesy....

Dense granular deposits on the endothelial side of the glomerular basement membrane (as depicted in the first, second, and third images below), on the outer aspect of the tubular basement membrane, or on both may be seen with electron microscopy in persons with LCDD. Classic ultrastructure examination findings include amorphous, noncongophilic, and nonfibrillar deposits. Most of these deposits are of kappa light chains (see the fourth image below). At times, the histologic changes are minimal, and occasionally glomeruli may have mesangial deposits. Rarely, glomerular crescents can also be seen in patients with LCDD.

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Light chain–associated renal disorders. Immunofluorescence (25X power) showing deposits of monotypic light chain along the basement membrane. Courtesy....

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Light chain–associated renal disorders. Ultrastructure (electron microscopy at 29,000X power) showing deposition of nonfibrillar electron-dense materi....

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Light chain–associated renal disorders. Ultrastructure (electron microscopy at 29,000X power) showing deposition of nonfibrillar electron-dense materi....

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Light chain–associated renal disorders. Immunoelectron microscopy (immunogold at 29,000X power) showing kappa light-chain deposition. Courtesy of Made....

Because many patients with LCDD do not have overt myeloma or any other evidence of monoclonal plasma cell proliferation, they may present with kidney disease manifesting with proteinuria, kidney insufficiency, or kidney failure. Therefore, the kidney biopsy findings may provide the first clues to the diagnosis of a monoclonal gammopathy.

Immunoglobulin light-chain amyloidosis (AL)

Kidney involvement is common in AL amyloidosis. In contrast to LCDD, in which the deposits are usually kappa light chains, the light chains involved in the formation of amyloidosis are usually of the lambda type. The histologic appearance of amyloid is usually quite distinctive and is confirmed easily using Congo red stains or by the ultrastructural demonstration of characteristic fibrils. AA amyloid loses its Congo red positivity when briefly exposed to potassium permanganate, while non-AA amyloid resists this treatment. In the kidney, a diagnosis of non-AA amyloidosis strongly suggests light-chain amyloidosis (AL).

Kappa light-chains are more likely to produce tubular dysfunction (Fanconi syndrome) and nodular nonamyloidotic glomerulosclerosis, while lambda light chains are more likely to be involved in the development of AL amyloidosis.

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Approach Considerations

Management of light-chain nephropathy depends on the underlying disease process. Take steps to limit further cast precipitation, and implement effective prevention and management of its complications. The goals of treatment are to prolong survival and to maintain quality of life.

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Medical Care

Proximal tubular dysfunction (Fanconi syndrome) and metabolic acidosis is treated with sodium bicarbonate therapy. Hypophosphatemia requires phosphate supplementation.

Distal renal tubular acidosis is treated with sodium bicarbonate therapy. Thiazide therapy (if no hypercalcemia is present) or correction of the  calcium level (if hypercalcemia is present) is used in patients with arginine vasopressin resistance (nephrogenic diabetes insipidus) and distal tubular dysfunction.

Amyloidosis is treated with pharmacologic therapy and autologous stem cell transplantation. Waldenström macroglobulinemia, if symptomatic, is treated with a variety of chemotherapeutic approaches; hyperviscosity syndrome in these patients requires plasmapheresis.

Multiple myeloma

The goals of therapy in patients with multiple myeloma and kidney failure are to optimize volume status; avoid and treat hypercalcemia, hyperuricemia, and infections; reduce the burden of light chains either by suppressing production with chemotherapy and/or removal of light chains with plasmapheresis or hemodialysis using high-cutoff dialyzers; and dialysis to correct complications of kidney failure, as per usual indications. For full discussion, see Multiple Myeloma Treatment Protocols.

Autologous stem cell transplantation

Myeloablative high-dose chemotherapy and autologous stem cell transplantation induce hematologic remission in a high proportion of patients with light-chain deposition disease (LCDD) who are eligible for such treatment, with durable long-term disease control.^[20] ​

ASCT can be effective in light-chain proximal tubulopathy (LCPT), delaying renal progression and minimizing the risk of recurrence after kidney transplantation. Stokes and colleagues reported on outcomes of 46 patients with LCPT treated between 2000 and 2014. Complete or very good partial hematologic remissions were achieved in one-third of treated patients, with lowest mortality and best hematologic outcomes seen in patients receiving ASCT.^[21]  

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Rare Causes of Acute Kidney Injury

Rare causes of acute kidney injury in patients with light-chain disorders, and the appropriate treatment, are as follows:

• Tumor lysis syndrome – Uric acid released following chemotherapy may precipitate in the tubules and may precipitate acute kidney injury. Hence, pretreating patients undergoing chemotherapy with allopurinol and diuresis is important.
• Nephrolithiasis and urinary tract infections – Infections of the upper and lower urinary tract are common in patients with multiple myeloma because of suppression of humoral immunity. Treat nephrolithiasis and urinary tract infections promptly.
• Hyperviscosity – Measure plasma viscosity in patients with clinical features of hyperviscosity; urgent plasmapheresis is required in such patients.
• Myeloma cell infiltration – Treat the underlying process.

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Treatment of Kidney Failure

Patients with kidney failure should have early, permanent vascular access because of the high risk of infection associated with temporary catheters. Refer the patient to a vascular surgeon for the placement of a permanent vascular access device.

Institute dialysis early to avoid uremia compounding the complications of underlying disease. Approximately 20% of patients die within the first month, but predicting which patients will die is not possible. Because 50% of the survivors live longer than 1 year and because recovery of kidney function is often delayed for several months, a policy of offering dialysis to most patients is justified. All patients with myeloma who present with acute kidney injury should receive dialysis.

Long-term dialysis (hemodialysis or peritoneal dialysis) should be considered for patients with chronic kidney disease and myeloma who are responsive to chemotherapy. Before instituting long-term dialysis therapy, consider the extent of other systemic disease. Patients who have progressive myeloma and do not respond to chemotherapy may not be candidates for long-term dialysis because their prognosis is very poor.

Acute kidney injury from cast nephropathy

The strong association between light-chain excretion and acute kidney injury suggests that light chains play a primary pathogenetic role in producing kidney damage. Renal recovery requires urgent intervention based on vigorous rehydration, correction of precipitating factors, and efficient anti–plasma cell chemotherapy to rapidly reduce the secretion of nephrotoxic free light chains. Currently, treatment with the proteasome inhibitor bortezomib and high-dose dexamethasone is the standard regimen for newly diagnosed patients with light-chain cast nephropathy.^[22]

Initially, small trials showed that therapeutic plasma exchange could improve renal outcomes in cast nephropathy.^[23] A randomized trial by Clarke et al^[24] in patients with acute kidney injury at the onset of multiple myeloma found that plasma exchange did not significant affect outcomes; however, this trial had several limitations, as there was substantial uncertainty regarding the diagnosis of cast nephropathy because only 61% of the patients had light chains in urine.^[25] A retrospective analysis of patients with a diagnosis of cast nephropathy with monitoring of serum light chains to guide therapy showed benefit for plasmapheresis in almost three quarters of the patients.^[26] Nevertheless, the published data are inconclusive in demonstrating benefit.^[27]

If plasma exchange is used, early and aggressive therapy with 5-7 exchanges within 7-10 days is recommended. The duration of therapy should be guided by serum free light chain measurement, with the goal of reducing light chains by a minimum of 60% for recovery of kidney function.^[28]

High-cutoff hemodialysis

Removal of serum free light chains with large-pore (25-50 kd) dialyzers rather than standard high-flux dialyzers was demonstrated in a pilot study of 19 patients with biopsy-proven myeloma kidney, in which 13 of the patients became dialysis-independent within 27 days.^[29] However, the phase 2 EuLITE study^[30] and the Multiple Myeloma and Renal Failure due to Myeloma Cast Nephropathy (MYRE) trial^[31] failed to show a significant benefit with high-cutoff versus conventional hemodialysis. Harding et al identified large free light chain aggregates above the cutoff of the dialyzer as a reason for failure of high-cutoff hemodialysis in these patients.^[32]

A systematic review and meta-analysis concluded that although high-cutoff hemodialysis may be able to reduce serum free light chains, it does not significantly improve all-cause mortality and renal outcomes compared with conventional hemodialysis for patients with myeloma cast nephropathy. However, the use of HCO dialysis was associated with a trend towards better renal outcomes.^[33]

Transplantation

Transplantation has been performed successfully in patients with end-stage renal disease secondary to multiple myeloma. Consider kidney transplantation only in patients who have achieved hematologic remission and who have no other major complications of their monoclonal gammopathy. Recurrent disease is common in patients with LCDD following transplantation, and kidney transplantation should not be done until optimal measures have ensured substantial reduction in light chain production.

Other measures

Treat infection early with non-nephrotoxic antibiotics. Intravenous immunoglobulin infusions have been used as prophylaxis against infection in the plateau phase of the disease.

Hyperviscosity may manifest as confusion and neurologic symptoms. Measure plasma viscosity in these patients, and implement urgent plasmapheresis.

Provide sodium bicarbonate supplementation to control acidosis.

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Consultations

A multidisciplinary approach is important in the treatment of these patients, and consultations with following specialists are useful:

• Hematologist/oncologist - Treatment of the underlying disease process
• Nephrologist - Prevention and treatment of acute kidney injury and chronic kidney disease; plasmapheresis
• Infectious disease specialist - Treatment of sepsis in immunocompromised patients
• Vascular surgeon - Placement of a permanent vascular access device for dialysis

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Diet

No special restrictions are required unless the patient has chronic kidney disease. Dietary considerations include the following:

• Optimize nutritional intake
• High fluid intake (2-3 L/d) is important to avoid dehydration and to minimize further cast formation
• Increased fluid intake is important during periods of volume depletion (eg, fever, diarrhea, vomiting)

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Prevention

Maintain adequate fluid intake (2-3 L/d), especially before initiating chemotherapy, to prevent dehydration. Dehydration and aciduria favors precipitation of light chains, which can cause acute kidney injury (AKI) in a significant number (up to 95%) of patients. 

Avoid nephrotoxic agents. Nonsteroidal anti-inflammatory drugs (NSAIDs), often used to relieve bone pain, are the most prominent offenders.

Ensure early and effective treatment of infections with nonnephrotoxic antibiotics. Intravenous immunoglobulin has been found to be safe when used as prophylaxis against infection in the so-called plateau phase.

Early recognition and treatment of hypercalcemia are important. Excessive calcium is an important cause of AKI in patients with myeloma and may be present in up to 30% of patients. Hypercalcemia impairs renal concentrating ability, thus leading to dehydration and promoting precipitation of light-chain proteins in renal tubules. Nausea, vomiting, and altered mental state associated with hypercalcemia further increase the likelihood of dehydration. Hypercalciuria also exerts a direct nephrotoxic effect and thus causes tubular degeneration and necrosis. Implement aggressive treatment of hypercalcemia, with saline diuresis, steroids, calcitonin, and diphosphonate.

Perform contrast studies judiciously in patients with multiple myeloma because of the possibility of contrast-induced AKI. However, McCarthy and Becker reviewed 7 retrospective studies of patients with myeloma who were receiving contrast media and noted that the incidence rate of AKI was only 0.6-1.25%, compared with 0.15% in the general population.^[34]

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Medication Summary

No standard treatment has been established for light-chain nephropathy, and the mainstay remains treatment of the underlying disease process and monitoring for complications and early recognition and management of complications.

In patients with myeloma, prevention of cast nephropathy is the mainstay by reducing the production of light chains by dexamethasone-based chemotherapy and promoting light chain filtration by volume status optimizaiton and intravenous fluid therapy to maintain urine volume of approximately 3 L/day, unless contraindicated, and alkalization of urine.

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Bortezomib (Boruzu, Velcade)

• Dosing, Interactions, etc.

Clinical Context:  First proteasome inhibitor approved for cancer therapy. The proteasome pathway is an enzyme complex existing in all cells. This complex degrades ubiquitinated proteins that control the cell cycle and cellular processes and maintains cellular homeostasis. Reversible proteasome inhibition disrupts pathways supporting cell growth, thus decreases cancer cell survival.

Bortezomib-based chemotherapy, in addition to early plasmapheresis, in patients with multiple myeloma and kidney failure secondary to myeloma cast nephropathy has been shown to achieve complete renal recovery in 40% of patients and is preferred therapy in this subset of patients.^[18]

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Melphalan (Alkeran (DSC), Evomela, Hepzato)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits mitosis by cross-linking DNA strands. Effective against both resting and rapidly dividing tumor cells.

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Vincristine

• Dosing, Interactions, etc.

Clinical Context:  Inhibits cellular mitosis by inhibiting intracellular tubulin function and binding to microtubules and spindle proteins in the S phase.

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Doxorubicin (Adriamycin, Caelyx, Rubex)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits topoisomerase II and produces free radicals, which may cause the destruction of DNA. The combination of these events can, in turn, inhibit the growth of neoplastic cells.

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Class Summary

The mainstay of treatment is effective control of the underlying (primary) disease. A combination of an alkylating agent (eg, melphalan) and prednisolone, administered for 4-7 d q4-6wk, is the standard first-line approach and induces remission in approximately 40% of patients. This combination does not act rapidly, and the dose of melphalan often must be modified because the drug is excreted via the kidney.

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Prednisone (Deltasone, Prednisone Intensol, Rayos)

• Dosing, Interactions, etc.

Clinical Context:  Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. Reduced to its pharmacologically active form, prednisolone.

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Dexamethasone (Baycadron, Decadron DSC, Dexamethasone Intensol)

• Dosing, Interactions, etc.

Clinical Context:  Potent glucocorticoid with minimal to no mineralocorticoid activity. Available in tablet and injectable suspension forms.

• References

Class Summary

Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

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