by ecancer reporter Vanessa Lane

Multiple myeloma (MM) is characterised by the malignant proliferation of plasma cells that usually produce a monoclonal immunoglobulin. Every component of immunoglobulin can cause kidney injury. These components injure the kidney via a number of mechanisms.

Renal dysfunction primarily results from the toxic effects of monoclonal light chains in the kidney. In the case of immunoglobulin light chains, precipitation and tubular obstruction is characteristic.

Normally, light chains are filtered by the glomerulus, reabsorbed and catabolised by the cells of the proximal tubule. In myeloma, the abundance of light chains overwhelms the capability of the proximal tubular cells, raising the concentration of light chains delivered to the distal tubule.

Deposition of immunoglobulins occurs either in the form of amyloid or non-amyloid, which can lead to the development of nonselective proteinuria. The characteristic finding of “myeloma kidney” is the presence of myeloma casts, composed mainly of light chains and Tamm-Horsfall protein in the distal tubules and collecting ducts. In proximal tubule cells, prolonged exposure to myeloma light chains induces apoptosis, DNA degradation and the production of the inflammatory and proinflammatory cytokines that initiate renal interstitial fibrosis and tubular destruction. Some myeloma patients present with acute oliguric renal failure. Acute cast nephropathy is generally associated with poor outcomes.

Serum creatinine >2.0 mg/dL represents one of the CRAB (calcium, renal [creatinine], anaemia and bone lesions) diagnostic criteria for symptomatic MM requiring therapy. However, serum creatinine is not directly related to renal function and depends on factors such as age, gender and muscle mass. The glomerular filtration rate (GFR) is a more accurate assessment parameter, providing a true reflection of renal function.

GFR in healthy subjects is considered to be in the range of 90-130 mL/min/1.73 m2. However, the standard method used to measure GFR is unsuitable in clinical practice due to the need for continuous infusion, multiple blood samples and expense. Creatinine clearance (CrCL) is another measure of renal function and is defined as the volume of plasma that is completely cleared of creatinine in a unit of time (usually mL/minute).

However, CrCL may overestimate GFR due to the additional tubular secretion of creatinine, a mechanism that becomes relatively more important when renal function declines. As a result, CrCL has been largely replaced by prediction formulas of GFR such as the C-G (Cockcroft-Gault) and MDRD (modification of diet in renal disease) study equations. Because the C-G and MDRD equations have limitations, especially in the normal or near-normal GFR range and in kidney transplant recipients, other prediction equations based on serum cystatin-C values may be more sensitive GFR surrogate markers. Cystatin-C is a sensitive endogenous marker of GFR. Estimating GFR based on both serum cystatin-C and serum creatinine seems to be more accurate than estimations based on serum creatinine alone. Other markers of renal injury have been investigated, including neutrophil gelatinase associated lipocalcin (NGAL) and kidney injury molecule-1 (KIM-1). NGAL is a protein that is overproduced by the proximal tubular cells in response to kidney injury. KIM-1 is over expressed in dedifferentiated proximal tubule epithelial cells after ischaemic or toxic injury.

In a recent study of patients with MM, nearly all patients (93%) had elevated urinary NGAL at diagnosis, while only 19% have elevated serum creatinine and 10% elevated urinary KIM-1, suggesting that tubular damage is present very early in the disease course. This is supported by the presence of elevated urinary NGAL in asymptomatic MM and MGUS and the correlation between urinary NGAL and the presence of serum free light chains. These latest results suggest that urinary NGAL and serum cystatin-C offer valuable information regarding kidney function in MM patients and may be a useful tool for identifying patients at high risk of developing future acute renal failure.