Dysproteinemias or light chain diseases

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 ).