Chapter 33. Plasma Cell Dyscrasias

The kidneys may be affected in a variety of ways in the plasma cell dyscrasias; all of the important lesions result from the accumulation/deposition of the paraprotein in some or all of the renal components (Table 33–1). The different abnormalities are determined by properties of the paraprotein rather than the patient response. The kidneys may be the only organ affected [the lesion known as Bence Jones (myeloma) cast nephropathy] or may be part of systemic processes (amyloidosis, monoclonal immunoglobulin deposition disease). A diagnosis of a plasma cell dyscrasia is not always known prior to the discovery of abnormal kidney function. The renal biopsy, performed to identify the responsible lesion, is not infrequently the initial indication of a plasma cell dyscrasia. Although multiple myeloma (MM) may be diagnosed, it is important to appreciate that some of the disorders discussed here may be associated with either a monoclonal gammopathy of uncertain significance (MGUS) or only a minor increase in bone marrow plasma cells. The clinical manifestations depend on the type of renal involvement, the renal tissue component affected, and whether only one or more of the lesions are present. The definition of the specific lesion is dependent on the tissue pathologic features, for the clinical and laboratory findings often do not readily allow for a specific diagnosis.

Essentials of Diagnosis

• Heavy proteinuria.
• Renal insufficiency.
• Monoclonal free light chains (LCs) in serum or urine.
• Renal biopsy disclosing characteristic extracellular deposits.

General Considerations

A contemporary classification of systemic amyloidosis (AL), based on the nature of the amyloid protein that is deposited in tissue, is given in Table 33–2. Amyloidosis is a disorder of abnormal protein folding in which normally soluble proteins are deposited in tissues as fibrillar structures that disrupt organ function and produce disease. The proteins are folded into a β-pleated sheet form that results in a high affinity for Congo red and several other metachromatic dyes. Only one variety of amyloidosis is also a paraprotein, namely AL amyloidosis, in which the fibrils are composed of one or the other of the immunoglobulin LCs. Although this discussion will focus on only this form of systemic amyloidosis, it should be recalled that amyloid may also occur in a localized form. Identification of the precise biochemical nature of the amyloid fibril requires the examination of a tissue specimen with a combination of immunofluorescence or immunoperoxidase and often biochemical tests. Genetic testing may also be needed in the case of the hereditary amyloidoses.

Amyloidosis is an uncommon disease affecting about 12 patients per million population per year, with about 15% representing hereditary forms and the remaining consisting of acquired, nongenetic forms. Any race, sex, or ethnicity can be affected.

Pathogenesis

AL amyloid fibrils are derived from the N-terminal region (variable domain) of monoclonal immunoglobulin LCs, more commonly λ than κ. The AL amyloid fibrils can deposit in almost any tissue except the brain. Certain LCs are more “amyloidogenic” than others. Furthermore, differences in the variable region of the LC (λ) may determine the sites of amyloid deposition. VλVI results in dominant renal involvement while others (VλII or III) are more likely to have dominant cardiac or other organ involvement. AL amyloidosis is also known as primary amyloidosis, largely a holdover from the older literature. A truncated monoclonal heavy chain may rarely cause amyloid (known as AH amyloid).

The fibrils in AL amyloidosis are composed of fragments of the variable portion of monoclonal LCs (λ more frequently than κ). In AA amyloidosis the fibrils are composed of the serum Amyloid A protein. In hereditary Amyloidosis the fibrils are composed of the mutant protein (e.g., Fibrinogen alpha chain). These can be differentiated by appropriate immunohistological studies of biopsy tissue (see below). As monoclonal LCs may deposit in tissue and result in another disease (see monoclonal immunoglobulin deposition disease), it is clear that an additional factor is necessary to form the characteristic morphologic features of amyloid. It is likely that the LCs need to be phagocytized by macrophages where the LCs are metabolized to preamyloid fragments that are secreted and precipitate in the tissues. In the kidneys, the major site of accumulation is the glomeruli, with arterioles, arteries, interstitium, and tubular basement membranes involved to somewhat lesser degrees.

Clinical Findings

Symptoms and Signs

Almost any B cell dyscrasia can be associated with AL amyloidosis, which develops in about 10–15% of cases of MM. Most cases of AL amyloidosis are not associated with MM, but rather develop in association with MGUS or as a “primary” disorder. A monoclonal paraprotein of free LCs can be detected in the serum or urine of the majority of patients. Because older patients may not infrequently (5–10%) have an MGUS, it is necessary to be cautious not to overinterpret the significance of a small paraprotein “spike” in a serum protein electrophoresis.

Bone marrow aspirates or biopsies may reveal frank MM, but frequently do not. The disorder develops equally in men and women, but is quite uncommon in individuals <40 years of age. The clinical manifestations, which depend on the site or sites of amyloid deposition, can be quite varied. Cardiac [heart failure due to restrictive cardiomyopathy, atrioventricular (AV) nodal disease, or “pseudoinfarct” or low-voltage patterns on EKG], renal (nephrotic syndrome, symptomatic proteinuria, renal failure), tongue (macroglossia), gastrointestinal (malabsorption, motility disorders), peripheral nerve [sensory (“stocking and glove”) and motor neuropathies, carpal tunnel syndrome], autonomic nerves (orthostatic hypotension, impotence, gastroparesis), skin (papules, nodules, purpura, ecchymoses with minimal trauma), joints (polyarthritis of the shoulder girdle), and coagulation (Factor IX and X deficiency with bleeding) are among the most common. Macroglossia is almost pathognomonic of AL amyloidosis. Patients presenting with unexplained proteinuria (including nephrotic syndrome), nonischemic cardiac failure, peripheral neuropathy, or hepatomegaly after age 40 years should always be suspected of having AL amyloidosis. Hypertension and hematuria are said to be uncommon in renal amyloidosis, but severe hypertension may be present when renal failure ensues, and normomorphic hematuria due to bladder involvement with amyloid may occur. Renal involvement is principally heralded by proteinuria, which sometimes can be massive (>20 g/day) and lead to problems of protein malnutrition, severe edema, and volume depletion.

The diagnosis of AL amyloidosis can be suspected on the basis of history and physical examination, but the diagnosis requires tissue confirmation. Biopsies of kidney (when proteinuria is present), abdominal fat pad aspiration, or rectal mucosal biopsies are preferred. Biopsy of an enlarged and firm liver in AL amyloidosis should be avoided because of the risk of bleeding. No such excessive bleeding risk appears to occur with a renal biopsy, unless the patient has a severe Factor IX or X deficiency.

Nonhistologic studies may be helpful but are not diagnostic. Cardiac ultrasound may reveal “sparkling” echogenicity and impaired contractility or relaxation of the ventricles in cardiac amyloidosis. Abdominal ultrasound studies often reveal normal sized or enlarged echogenic kidneys. Renal vein thrombosis may be detected by computed tomography (CT) or magnetic resonance imaging (MRI) in patients with the nephrotic syndrome.

Since serum amyloid P (SAP) component is universally present in amyloid (AL as well as other types), radioisotope-labeled SAP (125I) has been used to detect amyloid deposits and to quantitate their changes or resolution with treatment; however, this test has very limited availability. Highly sensitive and specific assays for circulating free LCs have also been developed and should be used for both diagnosis and follow-up of patients with AL amyloidosis to assess the “burden” of LCs.

Pathological Findings

The light microscopic features of amyloid are characterized by the infiltration of extracellular sites by pale-staining acellular amorphous material that is Congo red positive and displays apple-green birefringence when viewed with polarized optics (Figure 33–1). By electron microscopy, amyloid is composed of fibrils that are nonbranching, usually randomly arranged, of indefinite length, and approximately 10 nm in thickness. By immunofluorescence (IF), AL amyloid most commonly stains for the λ LC (approximately 75%) and less frequently for the κ LC; the pattern is of continuous amorphous or smudgy positivity. While these IF findings are generally the experience of many laboratories, a recent report has indicated that IF has a low degree of sensitivity for detecting a monoclonal LC.

The glomeruli are almost always involved. The amyloid deposits in mesangial regions, infiltrating and replacing mesangial matrix and compressing and displacing cells, and sometimes results in a nodular appearance; it also infiltrates and replaces capillary basement membranes.

Differential Diagnosis

Once a tissue diagnosis of amyloidosis is established, there is no differential diagnosis of the type of kidney disease. However, the precursor protein needs to be established. Once an abnormal LC (or heavy chain) is documented in the tissue deposits and/or in serum, urine, or in bone marrow or other plasma cells, there are no further diagnostic considerations.

Treatment

Treatment of AL amyloidosis is generally quite disappointing, but the outlook may be improving. In addition to supportive and symptomatic therapy, an attempt should be made to reduce the amount of amyloidogenic LC being produced. Oral melphalan (0.15 mg/kg/day for 7 days) and prednisone oral melphalan (20 mg three times per day for the same 7 days), repeated every 6 weeks depending on leukocyte counts, can slow the progression of the disease with a median survival of over 7 years in “responders” (reduced proteinuria, decreased amyloid “burden” in organs, and reduced circulating LC or monoclonal protein, if present).

All long-term survivors of AL amyloidosis have shown some objective response to chemotherapy, but unfortunately the majority of patients do not respond to melphalan-prednisone therapy. α-Tocopherol and interferon do not appear to be effective. High-dose dexamethasone plus interferon may yield some responses. 4′-Iodo-4′-deoxydoxorubicin has been effective in small studies, but the improvement in visceral amyloid deposits (VAD) has not been impressive. VAD regimens (previously described) have also been used in patients with AL amyloidosis (with and without MM) with benefits that seem to exceed those of the “standard” melphalan-prednisone therapy, at least in some studies. Thalidomide and its congeners, which are being evaluated for efficacy and safety in the treatment of MM, might also be effective in AL amyloidosis.

The most encouraging results have been seen with high-dose intravenous melphalan therapy followed by autologous bone marrow or peripheral stem cell transplantation; this may now be the treatment of choice for younger patients with limited organ system involvement, especially without cardiac involvement. However, recent controlled trials seem to indicate that the advantage of high-dose melphalan-prednisone plus autologous bone marrow transplantation therapy over high-dose melphalan-prednisone therapy alone for Systemic AL Amyloidosis is not as great as it was believed. Melpalan-prednisone plus autologous stem cell transplantation was not superior to high-dose melphalan-prednisone alone in this pivotal advanced study of advanced AL Amyloidosis. Stem cell transplants are very risky, with fatal outcomes common in patients with multisystem involvement and those with cardiac disease. Fractional survival for patients with two or fewer systems involved is about 75% at 5 years and is 25% or less at 2 years in those with cardiac involvement or more than two systems involved. Unfortunately, at present, the eligibility criteria for transplantation are such that only a minority of patients actually receive transplants. The best results are in patients with renal involvement as the sole or major manifestation of amyloidosis. Response duration and survival posttransplantation are superior to melphalan-prednisone treatment. A retrospective survey of over 700 patients with AL amyloidosis deemed “eligible” for high-dose intravenous melphalan and autologous stem cell transplantation revealed that only 44% actually received transplants and the median survival was 4.6 years; a complete hematologic response (disappearance of any evidence of a plasma cell dyscrasia) was achieved in 40% of patients. Mortality in the first 100 days was about 13% and was highest in those with cardiac involvement. The overall quality of life was greatly improved in those who achieved a complete hematologic and biochemical remission. Cardiac and/or renal allotransplantation has been performed, with anecdotal reports of prolonged survival. In the absence of specific therapy for the production of LC, recurrence of disease in the allograft can be anticipated.

General supportive therapy includes diuretics (for edema of nephrotic syndrome). Antihypertensive (angiotensin II inhibitors) agents should be used with great caution. Analgesics may be needed for neuropathic pain. Postural hypotension may limit the use of agents for hypertension present in the supine position. Midoridine and antigravity stocking may be of some benefit for severe postural hypotension. Cardiac glycosides (digoxin) and calcium channel antagonists are contraindicated, as they may worsen the cardiac manifestations.

Prognosis

The prognosis of AL amyloidosis, either in association with MM or as a “primary” disease, is poor, especially in the presence of clinically overt renal and/or cardiac involvement. In patients with renal involvement, the median time from diagnosis to end-stage renal disease (ESRD) is about 1 year and survival after dialysis is commenced is short, usually also less than 1 year. With current management, the principal cause of death is cardiac. In patients with restrictive myocardial disease (as determined by Doppler echocardiography), the 1-year survival is <50%. A low κ/λ ratio in bone marrow plasma cells may indicate a poor prognosis.

Essentials of Diagnosis

• Heavy proteinuria.
• Renal insufficiency.
• Hypertension.
• Monoclonal immunoglobulin (LC, heavy chain, both) in serum and/or urine.
• Renal biopsy with characteristic findings including extracellular deposition of paraprotein in in the basement membranes of glomeruli and tubules.

General Considerations

It is well recognized that several portions of the immunoglobulin molecule can deposit in the kidneys and elsewhere (largely in basement membranes) and result in homogeneous or microgranular “deposits” by electron microscopy. Initially considered the result of deposition of an abnormal κ LC resulting in what was initially termed LC deposit disease (LCDD), this systemic disorder has been expanded to include λ LC, heavy chain deposition (HCDD), and intact monoclonal immunoglobulin deposition (LHCDD). While many of these patients have multiple myeloma, monoclonal immunoglobulin deposition disease (MIDD) can develop in the absence of overt MM. POEMS, or the Crow-Fukase syndrome or Tatasuke syndrome, is an unusual variant that can be associated with a peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. Sclerotic bone lesions or Casteleman's disease commonly coexists. Papilledema, effusions, ascites, and thrombocytosis may appear.

Pathogenesis

In MIDD, most information about pathogenesis concerns LC deposit disease because it has been studied longer and is more common than heavy chain or LC and heavy chain deposit diseases. This discussion on pathogenesis will be related largely to LCDD. In a conceptual sense, this disorder is similar to amyloid in that it represents the systemic deposition of a paraprotein, with important pathologic and clinical manifestations in the kidneys. However, the LCs do not have the biochemical characteristics to change to a β pleated sheet configuration, form fibrils, and bind to Congo red stain. In contrast to amyloid, κ rather than λ is the predominant monoclonal protein and the tissue deposits are granular, not fibrillar. The factors that favor LC structure at deposition are not well understood; these may include degradation by macrophages, intrinsic properties of the intact LC, etc. Some MIDDs are associated with organized (fibrillar, crystalline or micro-tubular) deposits by electron microscopy. These include immunotactoid glomerulopathy, crystal cryoglobulinemia, and various forms of monoclonal cryoglobulinemia.

Clinical Findings

Symptoms and Signs

MIDD represents a broad spectrum of clinical presentations and findings. LCDD is the most common form, representing about two-thirds of all cases. HCDD and LHCDD have about equal frequency and together represent about one-third of the cases. Intact IgG deposition is least common. LCDD is frequently (about 50%) accompanied by myeloma cast nephropathy (MCN). In HCDD the deposits are most often composed of γ chain while in LHCDD the deposits are composed of either IgGκ or IgGλ. In the uncommon intact monoclonal IgG DD, the deposits are composed of IgG subclass 1, 2, or 3 and the κ/λ ratio is about 1:1.

All subcategories of MIDD have a similar presentation; however, severe dialysis-requiring renal failure, including acute renal failure (ARF), is more common in LCDD complicated by myeloma cast nephropathy. Nephrotic-range proteinuria and an impaired glomerular filtration rate (GFR) are very frequently observed in MIDD without myeloma cast nephropathy, but heavy glomerular proteinuria is infrequent in LCDD associated with myeloma cast nephropathy. At the time of diagnosis, over 95% of patients have a serum creatinine over 1.2 mg/dL. Hypertension is very common, but somewhat less frequent in patients with LHCDD. The gender ratio is about 1:1. Most patients are over 50 years of age at the time of diagnosis. Patients with HCDD and deposition of the intact monoclonal IgG molecule may often have a “false-positive” antibody test for hepatitis C viral infection and hypocomplementemia (C3, C4, or C′ H50). Liver function tests are normal in this circumstance. Serum or urinary protein electrophoresis for monoclonal proteins may be positive, more commonly in LHCDD and in HCDD (70–80%) than in LCDD (about 25%). A minority of patients will fulfill diagnostic criteria for multiple myeloma. A diagnosis of MM is more common in LCDD, almost always when myeloma cast nephropathy is also present. Some patients (60–70%) with HCDD or LHCDD will have an MGUS and others (10%) will have no identifiable B cell neoplasia. Hypogammaglobulinemia is common. The MIDD associated with cryoglobulinemia may have many systemic manifestations including hypocomplementemia, palpable purpura with cutaneous leukocytoclastic vasculitis, skin necrosis and alveolar hemorrhage. Immunotactoid glomerulopathy commonly presents as a renal-limited disease with hematuria and the nephrotic syndrome.

Pathological Findings

The hallmark of diagnosis is the documentation, by immunofluorescence, of only the abnormal LC (or light and/or heavy) chain in all basement membranes and other extracellular matrix in a continuous pattern. The κ LC is considerably more common than the λ LC in producing this disease (Figure 33–2A). The constant region of the immunoglobulin is typically deposited, resulting in strongly positive immunofluorescence for the monoclonal LC. In the kidneys, the tubular basement membranes, glomeruli, arterioles, and arteries are affected pathologically and clinically. This results in variable light and electron microscopic appearances. Some reports have indicated that the tubular basement membranes are more frequently affected than those in the glomeruli. However, the glomeruli are the major sites of clinical importance. The morphologic appearance of the glomeruli is typically considered to be of a nodular “glomerulosclerosis” with great similarity to the diabetic lesion (Figure 33–2B). However, there is considerable variation in appearance, especially in relation to the coexistence of Bence Jones cast nephropathy. Thus, glomeruli may have a normal appearance, may display mild or greater widening of the mesangium with or without increased cellularity, may have a membranoproliferative glomerulonephritis pattern of injury, and may have crescents or may have segmental sclerosis; consequently, the morphology of glomeruli is not an important diagnostic consideration. Glomeruli may be normal or near normal when the cast nephropathy coexists. By electron microscopy, there are continuous electron-dense coarsely granular deposits in capillary basement membranes and in mesangial matrix in glomeruli. This feature tends to be absent unless the nodular morphology is present. The tubular basement membranes are often thick and refractile by light microscopy and have ultrastructural findings similar to those in the glomeruli. Once again, the electron-dense “deposits” are not universally present. The MIDD with organized deposis uniformly have structural lesions by electron microscopy that differ from those described above. These are often referred to as non-Randall-type deposits, as the amorphous or granular deposits associated with the Light chain deposition diseases are referred to as Randall-type deposits.

Differential Diagnosis

This is very limited; the diagnosis is established by renal biopsy and, given the diagnostic immunofluorescence and electron microscopic findings, the differential diagnosis is quite limited.

Treatment

With such a poor prognosis, aggressive treatment measures have been employed in most cases. If MM is diagnosed, therapy with intermittent melphalan plus steroids or a vincristine–adramycin–dexamethasone (VAD) regimen is indicated. Similar regimens have also been employed in patients without overt MM. While some may respond to these therapies, it is difficult to determine in advance which patients will benefit. Those with ESRD clearly respond poorly or have complications to these regimens. Plasma exchange has been tried in some patients, mostly in those with protein electrophoreses showing a large amount of circulating paraprotein. Bortezomib (Velcade) is gaining favor over melphalan-prednisone regimens for treatment of overt Multiple Myeloma in patients who are ineligible for high-dose Melphalan regimens.

Younger patients without ESRD or major comorbidities who have MM may also become candidates for bone marrow or autologous peripheral stem cell transplantation. The treatment of choice for POEMS is also high-dose chemotherapy with autologous peripheral stem cell transplantation. Intravenous IgG and plasmapheresis are not effective therapies for POEMS. MIDD has a propensity to recur in renal transplants usually within 3 years following transplantation. Measures to control the synthesis of the monoclonal proteins (high-dose chemotherapy) should precede transplantation in all cases; careful monitoring of LC or heavy chain production (serum levels) should be regularly conducted posttransplantation.

Prognosis

The outcome is poor in most cases, with death or ESRD in the majority of patients. The mean time to ESRD is <6 months in LCDD and myeloma cast nephropathy and is somewhat longer in MIDD without myeloma cast nephropathy. Renal survival in pure MIDD has been estimated to be about 50% at 2 years, whereas it is only about 10% or less in MIDD with myeloma cast nephropathy (LCDD). Patient survival has been estimated to be about 75% at 2 years in pure MIDD, but is only 40% or less at 2 years for MIDD with myeloma cast nephropathy.

Essentials of Diagnosis

• Acute or less commonly chronic renal failure.
• Monoclonal LC in serum and/or urine.
• Renal biopsy with characteristic tubular casts with fracture lines or fragmentation surrounded by multinucleated foreign body giant cells and composed of the abnormal LC.
• Multiple myeloma.

General Considerations

Myeloma cast nephropathy had been considered synonymous with renal involvement in multiple myeloma and was formerly known as “myeloma kidney.” However, with the definition of other lesions, including MIDD, it has become necessary to indicate the specific abnormality, as therapies and prognoses are different as indicated in the previous discussions. Thus, “myeloma kidney” is no longer a useful term. Bence Jones cast nephropathy may be the initial manifestation of multiple myeloma as ARF is often the presenting feature of this lesion.

Pathogenesis

Cast nephropathy results from the filtration of free monoclonal LCs by the glomeruli and their precipitation with Tamm–Horsfall protein in the distal nephron. It should be pointed out that while the distal nephron is a favored site of cast formation, the LCs may precipitate in any segment of the nephron, including the urinary spaces of glomeruli, presumably in the absence of Tamm–Horsfall protein. The monoclonal LCs are tubulotoxic, resulting in acute tubular necrosis. With subsequent destruction of the tubular walls in association with cast formation, an inflammatory process in the form of a foreign body reaction ensues and the casts are surrounded by multinucleated giant cells (Figure 33–3). The casts may be fragmented, crystal-containing, and have a brightly stained appearance; by immunofluorescence, the casts are composed of a single LC, the Bence Jones protein. It is this constellation of tissue findings that is almost pathognomonic of multiple myeloma and allows the pathologist to be the first to diagnose this marrow disorder by examining a renal biopsy performed in the work-up of ARF. As the casts are large, intranephron obstruction contributes to renal functional impairment.

Clinical Findings

Myeloma cast nephropathy is characterized by renal failure, including ARF, and high levels of urinary excretion of monoclonal LCs. It may represent the first manifestation of multiple myeloma and unless it is considered in the clinical differential diagnosis and unless a search for a paraprotein is not done, it is the renal pathologist who is responsible for establishing the diagnosis.

In the patients with ARF, a bland urine sediment, and negative or trace-positive dipstick for protein, urine protein should be evaluated by sulfosalicylic acid (SSA). The dipstick primarily detects albumin, not LCs; SSA detects nonalbumin proteins. Cast nephropathy without coexisting amyloid or MIDD is not associated with glomerular proteinuria (albumin).

Differential Diagnosis

Although Bence Jones cast nephropathy, as defined above, is pathognomonic of multiple myeloma, similar pathologic features have been described in B cell lymphoma and Waldenström's macroglobulinemia, both reflecting excretion of monoclonal LCs. Similar light microscopic cast morphology has been observed in some patients with pancreatic acinar cell carcinoma and renal transplants treated with tacrolimus and rapamycin; however, monoclonal LCs are not a component of casts in these settings.

Treatment

Myeloma cast nephropathy may respond to fluid volume expansion and increased water intake and a forced diureses (loop acting diuretics). Hypercalcemia (in MM), exposure to radiocontrast agents, nonsteroidal anti-inflammatory drugs (NSAIDs), diuretic-induced volume depletion, and hyperuricemia may all aggravate or precipitate an episode of MCN. It may also respond to loop-acting diuretics and to measures designed to decrease the production rate of LCs. Plasma exchange to reduce the levels of free LCs in the circulation in connection with an episode of ARF has been used to treat MCN, but the results are inconsistent and this procedure cannot be routinely recommended unless a hyperviscosity syndrome can be well documented.