Article Update

Tuesday, July 14, 2020


Multiple myeloma is a malignant disorder of plasma cells that features clonal proliferation of a single immunoglobulin-producing cell. These plasma cell clones hypersecrete monoclonal (M) proteins, which can be either intact immunoglobulins, usually of the IgG or IgA type, or free  or  light chains (known as Bence-Jones proteins). The disease is generally diagnosed during the sixth decade of life, and up to half of patients will experience renal complications. Renal disease typically occurs as a result of the hypersecretion of free light chains, which have a direct toxic effect on the kidneys; however, urate nephropathy and direct plasma cell infiltration of the renal parenchyma can occur as well.


Plasma cells normally release a modest excess of free light chains that are excreted in urine at the rate of 10 to 30 mg/day. These proteins are filtered at the glomerulus, and the majority are reabsorbed by proximal tubular cells and subsequently catabolized.
In multiple myeloma, light chains may be present in such overwhelming excess that they overcome the reabsorptive capacity of the nephrons. The high concentrations of light chains in the tubular lumina may in turn lead to a phenomenon known as “cast nephropathy.” Injury occurs through two mechanisms. First, light chains form obstructive casts that can cause acute or chronic renal failure. Second, light chains accumulate in proximal tubule cells because of resistance to degradation, which leads to tubular epithelial cell injury (and, in turn, impaired proximal light chain reabsorption and increased delivery to the distal tubule).
The formation of light chain casts is dependent on several factors. First, the light chains must reach a threshold concentration. Second, the light chains must bind to Tamm-Horsfall protein, normally produced in the thick ascending limb. Light chain casts are thus usually found in the distal tubule because of the increased light chain concentration in this segment (secondary to fluid reabsorption in more proximal segments), as well as the presence of Tamm-Horsfall protein.
Several factors can precipitate cast nephropathy in a patient with myeloma. Many of these factors either reduce glomerular filtration rate (GFR) or slow the rate of distal tubular fluid delivery, thereby raising the concentration of tubular light chains and favoring cast formation. For example, NSAIDs, ACE inhibitors, intravenous contrast, and infection can precipitate cast nephropathy, likely by decreasing GFR. Likewise, diarrheal illness, hypercalcemia, and diuretics are precipitants that likely act by causing volume depletion.
Less commonly, the M proteins may deposit in the glomerulus, where they disrupt the protein filtration barrier (e.g., light chain deposition disease, amyloidosis, and immunotactoid glomerulonephritis). In addition, the light chains may sometimes cause extensive damage to the proximal tubule, resulting in more generalized reabsorption defects (renal Fanconi syndrome).

Nearly 50% of patients with myeloma cast nephropathy have acute kidney injury; the remaining cases are either subacute or chronic. A typical presentation in a patient without known myeloma is several weeks of oliguria, weakness, fatigue, lethargy, and lower extremity edema with newly diagnosed severe renal insufficiency. In cotrast, a patient with a known myeloma diagnosis will often be noted to have an asymptomatic rise in creatinine on routine laboratory evaluation. Some of the known precipitants, listed previously, may be noted in the recent clinical history.
On further evaluation, patients will be found to have bland urine sediment, minimal dipstick proteinuria, and subnephrotic-range proteinuria on a quantitative collection. The dipstick measurement of proteinuria is generally unremarkable because it detects only albumin, whereas these patients excrete large quantities of light chains. Photometry of a urine specimen after the addition of a precipitant such as sulfosalicylic acid or tri- chloroacetic acid, however, will reveal the presence of all urine proteins. More than a gram of protein on a quantitative photometric urine specimen with a negative dipstick for albumin is suggestive of paraproteinuria. Immunofixation electrophoresis of serum and urine should be performed to confirm and identify the paraproteins.
In contrast, a strongly positive dipstick and nephroticrange proteinuria in the setting of myeloma suggests AL amyloidosis or light chain deposition disease, since these conditions cause glomerular injury that allows albumin to enter the urinary space.
The definitive diagnosis of myeloma depends on the observation of a monoclonal protein on serum or urine protein electrophoresis, demonstration of 10% or more clonal plasma cells on bone marrow biopsy, and evidence of organ damage. Recently, the ability to quantify free light chains has provided a more sensitive diagnostic modality. In multiple myeloma and other monoclonal gammopathies, overexpression ofκ or λ restricted light chains causes the κ:λfree light chain ratio to become abnormal.
Although cast nephropathy is highly probable in a patient with confirmed myeloma who has renal failure, a bland sediment, and minimal albuminuria, a definitive diagnosis requires renal biopsy.
The exact indications for renal biopsy are controversial. If one is performed, characteristic findings include intratubular casts that have a “fractured” appearance, with adjacent reactive cells that include multinucleated giant cells. On immunofluorescence, these casts stain only for κ or λ light chains, which corresponds to the abnormal light chain. Patients with more chronic disease may have a variable degree of tubulointerstitial fibrosis.


Treatment of myeloma cast nephropathy centers on volume expansion, which reduces intratubular cast concentration, as well as chemotherapy (and sometimes plasmapheresis), which reduces serum free light chain concentration. The role of plasmapheresis is controversial. One study of patients with biopsy-proven myeloma cast nephropathy found that plasmapheresis led to a 50% reduction in serum creatinine concentration, as well as dialysis independence, in those who experienced a more than 50% reduction in the serum free light chain concentration. Other studies, however, have shown no benefit. Dialysis is offered to patients who have advanced renal failure as a supportive measure, but it does not influence the course of the disease.

Survival in patients with multiple myeloma is inversely correlated with serum creatinine concentration at presentation, as shown in a study from the 1980s that found a median survival of 44, 18, and 4.3 months in patients with creatinine less than 1.4, 1.4 to 2.0, and greater than 2.0 mg/dL, respectively. The potential for improvement of renal function in response to treatment correlates best with the degree of tubulointerstitial fibrosis and tubular atrophy on biopsy. Recovery of renal function has been known to occur in patients who require dialysis, occuring up to 3 months after dialysis onset. a more than 50% reduction in the serum free light chain concentration. Other studies, however, have shown no benefit. Dialysis is offered to patients who have advanced renal failure as a supportive measure, but it does not influence the course of the disease.

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