Light Chain-Associated Renal Disorders

Practice Essentials

Light chains (molecular weight 22,000 d) are polypeptides that are synthesized by plasma cells and form part of immunoglobulins. 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.

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. 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 (BJP) 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.^[1] The term has 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 include the following:

• Monoclonal immunoglobulin deposition disease (MIDD)
• Light-chain, heavy-chain, and 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. 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 the following:

• Asymptomatic light-chain proteinuria
• Proximal tubular dysfunction (ie, Fanconi syndrome)
• Chronic kidney disease or acute kidney injury
• Light chain deposition disease (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 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; depending on the site of action, this may result in the following:

• Fanconi syndrome (proximal tubular dysfunction)
• Distal renal tubular acidosis
• Nephrogenic diabetes insipidus

Light chain deposition disease

Light chain deposition disease (LCDD) is a systemic disease caused by the overproduction and extracellular deposition of monoclonal light chains.^{[2, 3]}

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 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). The constant region of the immunoglobulin light chain is deposited in this disorder, compared with the fibrils of AL amyloid that are derived from the variable region of the light chains.^[4]

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 the following:

1. The direct toxicity of the intact light chains to tubular cells (compared with light chain fragment deposition in light chain deposition disease or amyloidosis)
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)
5. 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.^[5]

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.^[6]

Amyloid is not a single substance, but a family of complex glycoproteins of variable composition that undergo transformation (misfolding) to from 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, 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 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 a fibrillar or granular deposition of a given monoclonal light chain are unclear and appear to be dependent on the biochemical properties or 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.^[7]

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 if 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.

Multiple myeloma (47-70%): 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)

Waldenström macroglobulinemia (30-40%) is usually with 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, adenocarcinoma of the pancreas, and medullary carcinoma of thyroid. Also, light-chain deposition disease, idiopathic BJP (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.

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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 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, 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%. 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.

BJB 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 BJP.

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. 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 kidney disease is quite common (30-60%).

Renal insufficiency may be indolent, chronic and progressive, or rapidly progressive. Renal insufficiency, a common manifestation of multiple myeloma, is present in more than 50% of patients.^[8]  In one study, the risk of renal failure was 7% in patients with daily light-chain excretion of less than 0.005 g, 17%, with excretion of 0.005-2 g, and 39% with excretion of more than 2 g.

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

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

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.^[8]  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.

Factors associated with a poor prognosis in patients with multiple myeloma include high tumor mass (burden), presence of hypercalcemia (serum calcium >12 mg/dL), interstitial fibrosis and tubular atrophy based on kidney biopsy findings and pancytopenia. This is indicated by a WBC count of less than 1000/µL, a hematocrit value of less than 30%, and a platelet count less than 50,000/µL. Other indicators of poor prognosis are plasma cell leukemia, previous treatment failure(s), lambda light-chain disease compared to kappa light-chain disease, and high beta2-microglobulin level. Levels higher than 6 mcg/mL suggest a worse prognosis (survival of approximately 26 mo) compared to levels of less than 6 mcg/mL (survival of approximately 52 mo).

Once renal insufficiency is present, the relationship between the degree of renal impairment and the duration of survival is dramatic.

• 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.

​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.

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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 renal failure.

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

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 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.

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.

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 three patients reported with lambda light-chain proteinuria.^[9]

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

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Physical

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. 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.

Perform the Putnam heat test or the sulfosalicylic acid (SSA) test (with Exton reagent) to help detect urinary light-chain proteins. The results from either test 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.

Urine immunoelectrophoresis

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

CBC 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 (FLC, Freelite) assay

Free light chains (FLC, quantitative assay) have been shown to be 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% of patients) for serum immunofixation (IFE) and in 83% of patients for urine IFE.^[10] The combination of serum IFE and serum FLC detected an abnormal result in 99% of patients. Serum free light assay is mainly helpful in monitoring response to therapy.^[11] In some patients with negative serum and urine electrophoresis for monoclonal protein, serum free light chain was helpful in establishing diagnosis.^[12]

 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.^[13]

Serum electrolytes, including serum bicarbonate

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

Urine for glucose

Glucosuria may be observed in the absence of hyperglycemia.

Nephrotic-range proteinuria

This may be present in patients with AL amyloidosis.

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.

Hepatic profile

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.^[14]  

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Imaging Studies

Renal ultrasound

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

Skeletal survey

Results 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 renal 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 shown 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.^[15]

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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 shown 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 renal disease manifesting with proteinuria, renal insufficiency, or renal failure. Therefore, the renal biopsy findings may provide the first clues to the diagnosis of a monoclonal gammopathy.

Immunoglobulin light-chain amyloidosis (AL)

Renal 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

The goals of treatment are to prolong survival and to maintain quality of life.

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.

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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 correct calcium level (if hypercalcemia is present) in patients with nephrogenic diabetes insipidus and distal tubular dysfunction.

Amyloidosis is treated with chemotherapy. Waldenstrom macroglobulinemia requires plasmapheresis for hyperviscosity.

Multiple myeloma

The goals of therapy in patients with multiple myeloma and renal 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 renal failure, as per usual indications.

Any of the following chemotherapy regimens can be used in patients with multiple myeloma:

• Melphalan and corticosteroids
• Combination chemotherapy - VAD (ie, vincristine, Adriamycin, dexamethasone), ABCM (ie, Adriamycin, carmustine [BiCNU], cyclophosphamide, melphalan), or MEVP (ie, melphalan, cyclophosphamide, vincristine, prednisone)^[16]
• Bortezomib, thalidomide, dexamethasone, doxorubicin
• Interferon alfa 2b

Autologous stem cell transplantation, allogenic or autologous

Myeloablative high-dose chemotherapy and autologous stem cell transplantation induce hematologic remission in a high proportion of patients who are eligible for such treatment, and early results from a limited number of patients suggest that the deterioration of renal function may be arrested and possibly reversed.^[17] ​

Stem cell transplant (SCT) is recommended for light chain proximal tubulopathy (LCPT) to delay renal progression and to minimize the risk of recurrence after renal 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 SCT.^[18]  

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Rare Causes of Acute Renal Failure

Tumor lysis syndrome

Uric acid released following chemotherapy may precipitate in the tubules and may precipitate acute renal failure. 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 Renal Failure

Patients with renal 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 renal 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 renal failure should receive dialysis.

Long-term dialysis (hemodialysis or peritoneal dialysis) should be considered for patients with chronic renal failure 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.

Plasmapheresis

The strong association between light-chain excretion and renal failure suggests that light chains play a primary pathogenetic role in producing kidney damage. Plasma exchange appears to be the most efficient way to rapidly remove large amounts of light chains and has been advocated by many over the last 15 years, but its efficacy has not been established convincingly.

Zucchelli et al reported significantly higher survival rates in patients treated with plasma exchange (66% vs 28%, P< .001).^[19] In another randomized prospective trial, Johnson et al found no significant difference in the number of patients whose renal function improved with this therapy; however, they noted that patients with severe renal failure improved with plasma exchange.^[20]

Clarke et al^[21] found no statistically significant difference in the outcomes in a randomized controlled trial; 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.^[22] 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,^[23] but the benefit of the published data is inconclusive and a well-designed prospective trial is recommended in the future.^[24] Complete renal recovery was observed in 40% of patients with early institution of plasmapheresis and bortezomib-based chemotherapy to treat myeloma.^[25]

Early and aggressive therapy with 5-7 exchanges within 7-10 days is recommended, and the duration of therapy should be guided by serum free light chains with the aim to reduce light chains by a minimum of 60% for recovery of renal function.^[26] Plasmapheresis should be performed in conjunction with dexamethasone and bortezomib-based chemotherapy to reduce light chain production.

High-cutoff dialyzer s

Removal of serum free light chains with large-pore (25-50 kd) dialyzers rather than standard high-flux dialyzers has been 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^[27] and 2 trials—European Trial of Free Light Chain Removal by Extended Hemodialysis in Cast Nephropathy (EuLITE) and Studies in patients with Multiple Myeloma and Renal Failure due to Myeloma Cast Nephropathy (MYRE)—are ongoing in Europe to further assess the efficacy of these high-cutoff dialyzers in myeloma kidney failure. In a recent report, by the original authors, high-cutoff dialyzers were found to be ineffective in removing free light chains due to formation of large FLC aggregates.^[28]

Transplantation

Transplantation has been performed successfully in patients with end-stage renal disease secondary to multiple myeloma. Consider renal 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 renal transplantation should not be done until optimal measures have ensured substantial reduction in light chain production.

Other

Treat infection early and effectively with nonnephrotoxic antibiotics. Intravenous immunoglobulin infusions have been used as prophylaxis against infection in the plateau phase of the disease.

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

Provide sodium bicarbonate supplementation to effectively 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 and chronic renal failure
• Infectious disease specialist - Treatment of sepsis in immunocompromised patients
• Blood purification specialist - Plasmapheresis
• 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 renal failure.

• 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. This is important in the precipitation of acute renal failure in a significant number (up to 95%) of patients. 

Avoid nephrotoxic agents. 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 acute renal failure 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 renal failure. However, McCarthy and Becker reviewed 7 retrospective studies of patients with myeloma who were receiving contrast media and noted that the incidence rate of acute renal failure was only 0.6-1.25%, compared to 0.15% in the general population.^[29]

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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 optimizing volume status and intravenous fluid therapy to maintain urine volume of approximately 3 L/day, unless contraindicated, and alkalization of urine.

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Bortezomib (Velcade)

• Dosing, Interactions, etc.

Clinical Context:  First drug approved of anticancer agents known as proteasome inhibitors. 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 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)

• 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 (Vincasar PFS, Oncovin)

• 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, 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, Meticorten, Orasone)

• 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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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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