Core Curriculum in Nephrology
Renal Manifestations of Plasma Cell Disorders

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Introduction

Plasma cell dyscrasias represent a group of diseases characterized by the clonal expansion of abnormal plasma cells. The result of this clonal expansion is the overproduction of a monoclonal (M) protein which could be either the whole immunoglobulin or a fragment (heavy or light chain alone). Thus, these disorders are also collectively referred to as monoclonal gammopathies.

The most common monoclonal plasma cell disorders are monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma, light-chain (AL) amyloidosis, and Waldenström macroglobulinemia (Table 1). MGUS and SMM are asymptomatic disorders that by definition lack end-organ damage. On the other hand, multiple myeloma is characterized by the presence of end-organ damage, most commonly anemia, hypercalcemia, renal failure, and osteolytic bone lesions. AL amyloidosis is a less common disorder that can affect any organ, the most common being heart (restrictive cardiomyopathy), kidney (nephrotic syndrome or renal failure), liver, gastrointestinal tract, and peripheral nerves. Waldenström macroglobulinemia is associated with an immunoglobulin M (IgM) monoclonal protein, and can cause hyperviscosity syndrome, anemia, lymphadenopathy, and hepatosplenomegaly.

Renal disease is particularly common in patients with monoclonal plasma cell disorders. Manifestations of renal disease vary depending on the mechanism of injury. This review will concentrate on light-chain cast nephropathy, immunoglobulin light-chain amyloidosis (AL), and monoclonal immunoglobulin deposition disease.

Section snippets

Renal Disease of Plasma Cell Dyscrasia

  • I

    Common

    • A

      Light-chain cast nephropathy (myeloma kidney)

    • B

      Immunoglobulin light-chain (AL) amyloidosis (also referred to as primary amyloidosis)

    • C

      Light chain deposition disease (LCDD)

    • D

      Light heavy chain deposition disease (LHCDD)

    • E

      Acute tubular necrosis

      • 1

        Drugs (nonsteroidal antiinflammatory drugs (NSAIDs), bisphosphonates)

        • i

          Bisphosphonates have been associated with acute renal failure in patients with and without multiple myeloma; both zoledronic acid and pamidronate have been associated with acute tubular

Additional Reading

  • 1

    Winearls CG: Acute myeloma kidney. Kidney Int 48:1347-1361, 1995

  • 2

    Markowitz GS: Dysproteinemia and the kidney. Adv Anat Pathol 11:49-63, 2004

  • 3

    Markowitz GS, Fine PL, Stack JI, et al: Toxic acute tubular necrosis following treatment with zoledronate (Zometa). Kidney Int 64:281-289, 2003

  • 4

    Ma CX, Lacy MQ, Rompala JF, et al: Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma. Blood 104:40-42, 2004

  • 5

    Nasr SH, Markowitz GS, Stokes MB, et al: Proliferative

Incidence of Monoclonal Gammopathy-Related Kidney Disease

  • I

    Varies depending on definitions

  • II

    In myeloma patients, renal insufficiency is noted in 18% to 56%

  • III

    At autopsy, renal involvement is seen in approximately 50% of patients with multiple myeloma

    • A

      Light chain cast nephropathy (29%-32%)

    • B

      AL amyloidosis (5%-11%)

    • C

      LCDD (3%-5%)

    • D

      Acute tubular necrosis

      • 1

        Common finding

      • 2

        Can occur alone or in conjunction with other pathologies

  • IV

    Less is known about the incidence of monoclonal gammopathy related kidney disease in patients without myeloma

  • V

    In patients who have significant

Additional Reading

  • 1

    Alexanian R, Barlogie B, Dixon D: Renal failure in multiple myeloma. Pathogenesis and prognostic implications. Arch Intern Med 150:1693-1695, 1990

  • 2

    Blade J, Fernandez-Llama P, Bosch F, et al: Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med 158:1889-1893, 1998

  • 3

    Rayner HC, Haynes AP, Thompson JR, Russell N, Fletcher J: Perspectives in multiple myeloma: survival, prognostic factors and disease complications in a

Mechanisms of Renal Injury

  • I

    Tubular precipitation

    • A

      Light chain cast nephropathy

  • II

    Deposition

    • A

      Amyloidosis

    • B

      Monoclonal immunoglobulin deposition disease (MIDD)

      • 1

        Light chain deposition disease

      • 2

        Light heavy chain deposition disease

      • 3

        Heavy chain deposition disease

    • C

      Crystalline nephropathy

    • D

      Fanconi syndrome

  • III

    Hyperviscosity

    • A

      Waldenström macroglobulinemia

    • B

      Myeloma with elevated serum concentration

      • 1

        IgM > 30 g/L

      • 2

        IgA > 60 g/L

      • 3

        IgG > 40 g/L

  • IV

    Glomerular reactions

    • A

      AL amyloidosis

    • B

      MIDD

    • C

      Membranoproliferative glomerulonephritis

    • D

      Immune complex mediate glomerulonephritis

    • E

Additional Reading

  • 1

    Sanders PW, Booker BB, Bishop JB, Cheung HC: Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 85:570-576, 1990

  • 2

    Teng J, Russell WJ, Gu X, et al: Different types of glomerulopathic light chains interact with mesangial cells using a common receptor but exhibit different intracellular trafficking patterns. Lab Invest 84:440-451, 2004

  • 3

    Myatt EA., Westholm FA, Weiss DT, et al.: Pathogenic potential of human monoclonal immunoglobulin light chains:

Light-Chain Cast Nephropathy

  • I

    Clinical features

    • A

      More likely in patients with high tumor burden (Durie-Salmon stage III)

    • B

      Acute onset of renal failure

    • C

      10% to 15% present with end stage renal disease

    • D

      Greater than 75% have sub–nephrotic range proteinuria

      • 1

        Mainly Bence-Jones proteinuria

      • 2

        Often dipstick negative

    • E

      Precipitating factors

      • 1

        Volume depletion

      • 2

        Hypercalcemia

      • 3

        NSAIDs

      • 4

        Intravenous contrast

      • 5

        Infections

  • II

    Pathogenesis

    • A

      Increased tubular concentration of light chains

      • 1

        Decreased uptake in proximal tubule

      • 2

        Increased serum concentration

    • B

      Binding and

Additional Reading

  • 1

    Knudsen LM, Hjorth M Hippe E: Renal failure in multiple myeloma: reversibility and impact on the prognosis. Nordic Myeloma Study Group. Eu J Haematol 65:175-181, 2000

  • 2

    Korbet SM, Schwartz MM: Multiple myeloma. J Am Soc Nephrol 17:2533-2545, 2006

  • 3

    Sanders PW, Booker BB: Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 89:630-639, 1992

  • 4

    Lacy MQ, Dispenzieri A, Gertz MA, et al: Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clinic

Monoclonal Immunoglobulin Deposition Disease

  • I

    Subtypes

    • A

      Light chain deposition disease (most common)

    • B

      Light heavy chain deposition disease

    • C

      Heavy chain deposition disease

    • D

      MIDD with cast nephropathy

    • E

      MIDD with amyloidosis

  • II

    Clinical features

    • A

      Renal involvement is nearly universal

      • 1

        Renal insufficiency

      • 2

        Proteinuria

        • i

          Nephrotic range in 40%

        • ii

          Usually dipstick positive

      • 3

        Hypertension

    • B

      Extrarenal manifestations present in 35%

      • 1

        Most common

        • i

          Cardiac – congestive heart failure

        • ii

          Liver – elevated liver enzymes

      • 2

        Less common

        • i

          Peripheral neuropathy, muscle wasting, carpel tunnel syndrome

        • ii

Additional Reading

  • 1

    Lin J, Markowitz GS, Valeri AM, et al: Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol 12:1482-1492, 2001

  • 2

    Pozzi C, D’Amico M, Fogazzi GB, et al.: Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 42:1154-1163, 2003

  • 4

    Heilman RL, Velosa JA, Holley KE, Offord KP, Kyle RA: Long-term follow-up and response to chemotherapy in patients with light-chain deposition disease. Am J Kidney Dis

Immunoglobulin Light-Chain Amyloidosis

  • I

    Background

    • A

      Historically known as primary systemic amyloidosis

    • B

      Usually caused by a monoclonal light chain (light-chain amyloidosis; AL)

    • C

      Rare cases of monoclonal heavy chain amyloidosis (AH) have been reported

  • II

    Clinical features

    • A

      Proteinuria

      • 1

        75% present with proteinuria

      • 2

        Can be massive > 20 g/d, nephrotic range in ∼ 30%

      • 3

        High concentration of albumin (dipstick positive)

    • B

      Renal insufficiency

      • 1

        Half present with reduced renal function

      • 2

        20% have serum creatinine > 2 mg/dL

    • C

      Hypotension

      • 1

        Often despite a previous history of

Additional Reading

  • 1

    Kyle RA, Gertz MA: Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol 32:45-59, 1995

  • 2

    Dember LM: Amyloidosis-associated kidney disease. J Am Soc Nephrol 17:3458-3471, 2006

  • 3

    Gertz MA, Lacy MQ, Lust JA, et al: Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis. Med Oncol 16:104-109, 1999

  • 4

    Kyle RA, Greipp PR, Garton JP, Gertz MA: Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine. Am J

Diagnostic Approach to Renal Dysfunction in Plasma Cell Dyscrasias

  • I

    Serum protein electrophoresis

    • A

      Monoclonal proteins will appear as a spike in the pattern (Fig 1)

    • B

      Sensitivity (500-2000 mg/L)

    • C

      May not pick up small bands or bands outside of the gamma region

  • II

    Urine protein electrophoresis

    • A

      Useful to determine the make up of the urinary protein

      • 1

        A high albumin content suggests a glomerular process

    • B

      Both serum and urine should be tested in increase detection to ∼95%

  • III

    Immunofixation

    • A

      Anti-serums to light and heavy chains are used to aid in the detection of monoclonal protein after

Additional Reading

  • 1

    Katzmann JA, Clark RJ, Abraham RS, et al: Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 48:1437-1444, 2002

  • 2

    Rajkumar SV, Dispenzieri A, Kyle RA: Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clinic Proc 81:693-703, 2006

  • 3

    Lachmann HJ, Booth DR, Booth

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