Dysproteinemias
1. What is myeloma?
Myeloma is a hematologic malignancy comprising about 1% of all cancers. It consists of an excess of clonally expanded cytogenetically heterogeneous bone marrow-derived plasma cells with two cardinal features: a monoclonal immunoglobulin (the paraprotein or M-protein) and/or associated light chains (LCs; kappa [κ] and lambda [λ]) with bone destruction that usually manifests as osteolytic lesions. All myeloma derives from a preclinical phase known as monoclonal gammopathy of unknown significance (MGUS). Myeloma is diagnosed when there is clonal expansion of bone marrow plasma cells >10% and any one myeloma-defining event using the CRAB criteria:
- •
Hyper c alcemia
- •
R enal insufficiency
- •
A nemia
- •
B one lesion
The most common class of whole immunoglobulin (Ig) is IgG followed by IgA and IgD. In approximately 20% of patients only an associated LC component is detected. It is a disease of the elderly, with the median age of diagnosis being older than 65 years of age. At diagnosis, there is evidence of kidney damage in nearly half of patients and up to 10% will have severe kidney failure requiring urgent dialysis. Kidney failure is most common in patients with IgD and LC myeloma.
2. How does myeloma cause acute kidney injury (AKI)?
- •
Cast nephropathy
- •
Hypercalcemia-induced volume depletion
- •
Monoclonal immunoglobulin deposition disease (MIDD)
- •
Amyloidosis
- •
Proximal tubulopathy/Fanconi syndrome
- •
Cryoglobulinemia
The use of kidney biopsy to distinguish between these potential etiologies and to guide therapy is frequently required.
3. What is cast nephropathy?
The most common histologic finding in myeloma is cast nephropathy (MCN), which is characterized by eosinophilic acellular fractured casts, with brittle cracks commonly in the distal tubules and collecting ducts, and—to a lesser extent—in the proximal tubules with epithelial cell necrosis and thinning and dilatation of the lumina. The casts are surrounded by inflammatory cells including macrophages, multinucleated giant cells, and polymorphonuclear neutrophils. There is interstitial edema and inflammation, and in the later stages interstitial fibrosis ( Fig. 39.1 ). The casts usually stain for a monoclonal LC. In some cases, casts are absent but the interstitial inflammation and fibrosis are present.
4. What can precipitate AKI in myeloma?
Patients with myeloma are particularly vulnerable to factors that cause volume depletion or sudden reductions in glomerular filtration. This is because these changes reduce tubular flow and increase the exposure of the tubule to high LC concentrations. Classically, hypercalcemia related to plasma cell-mediated bone destruction and the release of calcium causes volume depletion and vasoconstriction, and is present in around 15% of patients at diagnosis. Non-steroidal agents prescribed for bone pain and intravenous contrast agents used for diagnostic investigations also abruptly reduce glomerular filtration and are associated with AKI, which is sometimes irreversible. Sepsis resulting from chemotherapy and reduced Ig levels may cause AKI.
5. What clinical and laboratory clues suggest myeloma as the cause of AKI?
The signs/symptoms of AKI due to myeloma are similar to typical AKI with a few additions. They may have malignant bone pain, which is often low back pain resistant to rest or simple analgesics. Myeloma should be suspected when the patient has any severe cytopenia (anemia, thrombocytopenia, or pancytopenia resulting from marrow invasion by plasma cells), relatively preserved albumin-corrected calcium (from bone release of calcium), immunoparesis (when all Ig classes are reduced), or an increased globulin fraction. Urinalysis, although important, may be misleading, because the increased urinary excretion of LCs associated with myeloma is not detected by testing for albumin (e.g., Albustix) but only for total protein (e.g., sulfosalicylic acid test) or by specific urine electrophoresis and immunofixation. The diagnosis of myeloma in AKI is now rapidly and preferentially made by the measurement of the serum free light chain (sFLC) ratio (see Question 12).
6. What specific laboratory diagnostic tests are used for the diagnosis of myeloma?
Serum protein electrophoresis (SPE) by separation of protein upon an agarose gel can detect the whole Ig in the range of 1 to 5 g/dL, but it only detects increased LC in patients who have very high levels of LC-only myeloma, and it is semi-quantitative. Serum immunofixation electrophoresis (IFE) is around 10 times more sensitive for Igs and LC, but it is not quantitative. Urine IFE requires concentrated urine samples for the detection of FLCs and can detect low levels of LC. The detection of urine LC by the primitive techniques of boiling and precipitation was one of the earliest descriptions of myeloma disease “mollities ossium” and its manifestations published in 1847 by Dr. Henry Bence-Jones. Subsequently Korngold and Lapiri (designated Kappa and Lambda) raised antisera against the two LC domains. Bence-Jones proteins are urinary FLCs detected by urinary protein electrophoresis and immunofixation.
7. Why measure serum FLCs?
Historically, the biochemical methods to diagnose myeloma, and especially LCs, via protein chemistry have been problematic, slow to perform, and lacked both sensitivity and specificity. In contrast, the measurement of serum FLC by nephelometry is rapid (hours); more sensitive (1 to 3 mg/L); and, along with an SPE (to determine the presence or a whole Ig component), will diagnose the majority of patients with myeloma, amyloidosis, and other MIDD and is now the preferred diagnostic test. An abnormal sFLC ratio (normal κ/λ 0.26 to 1.65) is due to an overproduction of a single κ or λ clone (with suppression of the other) and this excess is detectable in the serum before urinary tubular catabolism is exceeded and before the SPE or IFE is abnormal. In patients with chronic kidney disease (CKD), significant accumulation of sFLC occurs (approximately fivefold) due to reduced excretion; so the normal range is adjusted to reflect this ( κ/λ 0.37–3.17) and reduces the over-diagnosis of monoclonal gammopathy in CKD. In patients with myeloma and severe AKI from MCN the sFLC always exceeds 1000 mg/L and the ratio is always abnormal. The measurement of urine FLC does not improve diagnostic yield, and the measurement of sFLC instead of urine IFE is now incorporated into hematologic guidelines. Serial measurements of FLC also provide real-time and quantitative monitoring of the response to chemotherapy and dialysis because of the short half-life (hours) of the sFLC compared to whole Igs (3 weeks) when measured by SPE.
8. Why are LCs toxic to the kidney?
Kidney injury is principally related to the LC component of myeloma because, unlike Igs, LC are freely filtered at the glomerulus and reabsorbed in the proximal tubule. Under normal conditions only small amounts of LC are filtered and reabsorbed, but in myeloma the amount of LC may rise to extreme levels that overwhelm the capacity and function of the proximal tubular cell (and induce proximal tubular injury) and pass to the distal tubule where they interact with uromodulin (Tamm-Horsfall protein) to form insoluble casts that obstruct the tubule, rupture the basement membrane, and induce an inflammatory response.
Recent data suggest that the cysteine residues present at the N and C termini of the FLC-binding domain are linked through an intramolecular disulfide bridge, which places the two histidine residues in close proximity to permit potential ionic interaction with the CDR3 domain of FLC. Capitalizing on this observation, a study analyzed this interaction and showed that the secondary structure and key amino acid residues on the CDR3 of the FLCs were critically important determinants of the molecular interaction with Tamm–Horsfall glycoprotein. These findings permitted the development of a strongly inhibiting cyclized competitor peptide. When used in a rodent model of cast nephropathy, this cyclized peptide construct inhibited cast formation and the associated functional manifestations of AKI in vivo. However, not all LC are toxic, and some patients can excrete large quantities without AKI. Specific molecular variants of the LC molecule form specific forms of kidney injury, such as myeloma cast nephropathy or amyloidosis.
9. What is the value of a bone marrow biopsy in patients with myeloma and AKI?
Bone marrow biopsy is performed to confirm marrow involvement by clonally expanded plasma cells and for the determination of cytogenetic abnormalities, which provide important prognostic information regarding treatment and outcome. The bone marrow shows displacement of the normal marrow by plasma cells, which ranges from complete replacement by sheets of tumor cells or as nodular aggregates. The mature plasma cells have eccentric nuclei with “clock-face” chromatin and plentiful cytoplasm, and the immature forms are pleomorphic with abnormal nuclear forms. Immunoperoxidase stains show the tumor cells to stain positive with CD138 and a monoclonal LC restriction ( Fig. 39.2 ).
10. When should I perform a kidney biopsy in patients with myeloma and AKI?
In patients with biochemically proven myeloma and AKI who do not show a prompt response to hydration and the correction of precipitants, a diagnostic kidney biopsy to determine the cause of kidney injury is suggested because of the variability in kidney etiology and the importance of ensuring a correct histologic diagnosis. In patients with an excess of albuminuria rather than the expected LC proteinuria, a biopsy is necessary to establish the presence of amyloidosis or other glomerular disorders associated with LCs. The type and stage of disease (especially the degree of tubular fibrosis) may influence the choice of chemotherapy and the consideration of adjunctive treatments such as high cut-off (HCO) dialysis. Sometimes, the diagnosis of myeloma is made or suggested by the kidney biopsy as the first investigation and subsequently confirmed with protein chemistry.
11. How do I treat myeloma cast nephropathy?
Myeloma cast nephropathy is a medical emergency and requires immediate diagnosis and early institution of therapy to prevent irreversible kidney failure. There are two key treatment strategies.
- •
The first is to remove any precipitants (e.g., sepsis, non-steroidal antiinflammatory drugs, hypercalcemia) and increase urine flow to reverse or prevent oliguria. The toxicity of LC in the tubules in part relates to their concentration, and increasing tubular flow reduces this. Volume expansion with normal saline (or sodium bicarbonate in the presence of acidosis) and the maintenance of a high urine flow (ideally 3 L a day) with adequate oral fluids are required. The reversal of hypercalcemia with volume expansion and bisphosphonates with reduced dosing and infusion rates (as a result of tubular toxicity in kidney injury) is also indicated. An alternative to bisphosphonates is denosumab, which is not nephrotoxic. The use of furosemide may worsen cast formation and induce volume depletion; it should be used with caution or avoided.
- •
The second key strategy is the early use of chemotherapy (see Question 12) to reduce the LC load. In all patients, dexamethasone, 20 mg bid, which induces apoptosis of plasma cells, can be immediately commenced to rapidly lower the serum LC load.
12. What chemotherapy is used in patients with myeloma and AKI?
Although myeloma and AKI are incurable, chemotherapy and the use of autologous stem cell transplantation (ASCT) have improved patient survival significantly. ASCT is now the procedure of choice for eligible patients and the avoidance of alkylating agents, such as melphalan, that impair stem cell harvest is preferred. Chemotherapy targeting rapid plasma cell killing and LC lowering should include the reversible proteasome inhibitor bortezomib (which does not need dose adjustment in kidney failure) alone or in conjunction with other agents. Lenalidomide, a derivative of thalidomide, has also shown great benefit for rapid lowering of LC, but it requires dose adjustment in kidney failure because of myelosuppression. Determining the optimal chemotherapy requires close collaboration between nephrologists and hematologists to individualize management decisions according to age and comorbidity, suitability for ASCT, eligibility for trials, and consideration of HCO dialysis.
13. Does plasmapheresis remove free LCs in myeloma?
Patients with AKI from myeloma cast nephropathy have very high circulating and tissue FLC because of uncontrolled production and impaired excretion. The reduction of this burden by enhanced non-kidney clearance while awaiting clinical benefit from chemotherapy may allow kidney recovery. Conventional dialysis has very low FLC clearance, and plasmapheresis was used to improve plasma clearance. The modeling of clearance suggests that plasmapheresis can reduce the FLC load, but because there is a high extravascular refilling and exchanges are limited to around 3.5 L volumes, it requires daily treatment. Comparison with daily dialysis using HCO membranes (see Question 14) suggests plasmapheresis is inferior, and clinical trials have not shown a benefit of plasmapheresis in MCN. Plasma exchange should be used only in patients with symptoms and signs of hyperviscosity (e.g., in IgA myeloma and Waldenström macroglobulinemia [WM]) when rapid lowering of whole Igs is required to alleviate symptoms.
14. What form of dialysis is best for patients with myeloma?
The use of dialysis is required in up to 10% of new patients with myeloma and AKI. Most often this is hemodialysis via central venous catheters. Until recently, only 15% of patients recovered kidney function, and there was a high mortality. However, long-term use of both peritoneal dialysis and hemodialysis has been used, and survival on dialysis, although reduced, depends on myeoma control by chemotherapy. Survival on dialysis is improved with increased response to newer chemotherapy agents. Kidney recovery with freedom from dialysis is associated with an even greater survival benefit. The use of HCO membranes for hemodialysis offers a novel method to remove large amounts of sFLC over extended dialysis (8 hours duration). In conjunction with chemotherapy, especially bortezomib, it is associated with kidney recovery rates of more than 70%. However, the true independent benefit of HCO, and its additional cost, when compared with the introduction of chemotherapy associated with rapid LC lowering alone, remains unproven by randomized clinical trial and therefore cannot be routinely recommended.
15. What is MGUS?
MGUS is defined as a paraprotein <3 g/dL, with <10% plasma cells in the bone marrow and no evidence of end-organ damage (no anemia, lytic bone lesions, hypercalcemia, or kidney disease attributable to the paraprotein). Nearly 3% of individuals older than age 70 have MGUS. About 1% of patients with MGUS progress to symptomatic myeloma each year, so annual follow-up is required. Patients with a higher level of paraprotein (>1.5 g/dL), non-IgG paraproteins, and an abnormal sFLC ratio at diagnosis are more likely to progress. Patients with MGUS usually have no or low levels of Bence-Jones proteins.
16. What is smoldering myeloma?
Smoldering myeloma is an intermediate clinical stage of disease between MGUS and myeloma that has a much higher risk of progression to myeloma than MGUS (10% year or more). It is defined as a serum monoclonal protein (IgG or IgA) >3g/dL or a urinary monoclonal protein >500 mg/24 h, and/or clonal bone marrow plasma cells between 10% and 60% AND the absence of any CRAB feature. The early initiation of chemotherapy in this patient group may be considered to reduce the risk of organ damage by progression to myeloma.
17. If I screen a patient with newly found kidney impairment and find a monoclonal protein, how do I know if he or she has myeloma-induced kidney disease?
Of people older than 70 years, 3% have MGUS; this age group also has a high disease prevalence of diabetes and hypertension. Therefore, screening for alternative causes for kidney dysfunction in this age group will find patients with MGUS. The duration of the clinical history of kidney impairment and the extent of diabetic complications are helpful in differentiating the cause. In general, patients with MGUS have low levels of monoclonal protein (<3 g/dL), a normal FLC ratio, an absence or low level of urine LCs, and no clinical evidence of myeloma (no osteolytic lesions, anemia, or hypercalcemia). In some cases, bone marrow or kidney biopsy may be required.
18. What is monoclonal gammopathy of renal significance (MGRS)?
MGRS is now used to define a group of B cell lymphoproliferative disorders and plasma cell disorders that do not meet criteria for myeloma, WM, or lymphoma/leukemia, yet lead to a histologically defined pattern of kidney injury directly attributable to the paraprotein or LC. In MGRS, the clonal expansion is often low and below any diagnostic threshold for malignancy yet the paraprotein or the LC component is associated with clinical disease of a heterogeneous and significant nature (e.g., amyloidosis, MIDD). Because they have not been previously considered a malignant disorder, this has restricted their access to therapy required for control of the clonal disorder and caused confusion with diagnosis and management. Separating them into a separate group allows better clinical management options and research focus.
19. What is waldenstrom macroglobulinemia (WM) and does it cause AKI?
WM is an IgM monoclonal-protein-secreting lymphoid and plasma cell malignancy. It usually manifests with anemia and fatigue, but it also may cause constitutional symptoms of fever, weight loss, and sweats; organ involvement with hepatosplenomegaly and lymphadenopathy; peripheral neuropathy; and features of hyperviscosity and cryoglobulinemia (rash). The diagnosis requires a monoclonal IgM protein and a bone marrow with >10% lymphoplasmacytic cell infiltration. Usually, the FLC component is kappa only, and urinary kappa LCs can be found in around 70% of cases. Kidney involvement with WM is uncommon and classic myeloma cast nephropathy is rare. Kidney involvement is glomerular and presents with hematuria/proteinuria, impaired kidney function, and rarely nephrotic syndrome. Histologically it takes the form of an immune-mediated glomerulonephritis with IgM deposition and/or features of cryoglobulinemia with intraglomerular thrombi. Treatment is delayed until patients develop significant end-organ damage or symptoms. Plasma exchange, rituximab, alkylating agents (chlorambucil), and the purine nucleoside analogues (fludarabine, cladribine) alone or in combination can be used.
20. Do plasmacytomas involve the kidneys?
Plasmacytomas are solitary lesions of clonal plasma cells in bone or soft tissues (especially the upper respiratory tract) without plasma cell involvement of the bone marrow or any other features of myeloma. Approximately 50% have a small monoclonal serum protein. They do not involve the kidneys, although they can progress to myeloma. Elevated sFLC ratio at diagnosis is associated with a higher risk of progression.
21. What is POEMS syndrome?
The acronym POEMS refers to
- •
P olyneuropathy
- •
O rganomegaly
- •
E ndocrinopathy
- •
M onoclonal protein
- •
S kin involvement
POEMS is a very rare disease and requires a monoclonal plasma cell disorder with a progressive sensorimotor peripheral neuropathy and at least one other key criterion, particularly the presence of Castleman’s disease (angiofollicular lymph node hyperplasia) or osteosclerotic myeloma. In general, kidney involvement is not a usual feature, but when kidney involvement is present, it is unrelated to LC deposition. Definitive therapy is uncertain but may involve radiotherapy and chemotherapy regimens directed toward the myeloma component.
22. What is amyloidosis?
Amyloidosis describes diseases characterized by the abnormal deposition of fibrils in extracellular tissues derived from an abnormal protein that is bound to serum amyloid P protein. When this abnormal protein is a LC (usually λ), it is known as primary or AL amyloidosis. Other causes include the hereditary/genetic (AH; e.g., transthyretin) or secondary amyloidosis when chronic inflammation (e.g., familial Mediterranean fever) is associated with increased serum amyloid A protein (AA amyloid). These fibrils form tissue deposits within the body, especially the kidney, heart, liver, nerves, and gut. Although associated with myeloma in around 10% of patients, the majority present with organ dysfunction as a result of tissue infiltration rather than bone destruction.
23. What are the histologic features of amyloidosis?
Macroscopically the kidneys are enlarged, firm, and pale, and may be waxy. On light microscopy AA and AL amyloid have the same morphologic features and involve mainly the glomerulus and blood vessels, with less involvement from the tubulointerstitium. The glomerular deposits are seen predominantly in the mesangium as amorphous acidophilic deposits, weakly periodic acid–Schiff positive and negative or weakly positive with Silver stain ( Fig. 39.3 A). There is usually extension of the deposits along the peripheral capillary wall and the deposits form delicate spikes on the outer surfaces. The classical diagnostic test is the Congo red stain, which shows an orange-red color and apple-green birefringence when examined by polarized microscopy. Potassium permanganate bleaches AA amyloid. Specific immunohistochemistry tests identify Ig LCs or amyloid A protein, with the majority of AL amyloidosis caused by lambda LC deposits. Electron microscopy shows the distinctive amyloid fibrils, which are non-branching, are randomly arranged, measure 9 to 12 nm, and have electrolucent cores but cannot distinguish between AA, AL, and AH amyloidosis (see Fig. 39.3B).
