Introduction
Multiple myeloma (MM) is a dreadful, blood-based cancer characterized by an abnormal accumulation of plasma cells in the bone marrow. These rogue cells produce excessive amounts of monoclonal immunoglobulin or light chain proteins, known as M proteins, which interfere with normal blood cell production, weaken bones, and damage kidneys. While advancements in research have introduced several treatment options, the quest for precise diagnostic markers and better therapeutic interventions continues. Interestingly, recent studies highlight a potent molecular player-Cystatin C, which can revolutionize the way we diagnose and treat MM-related complications, particularly those affecting the kidneys and bones.
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Fig. 1 Changes of serum and urine cystatin C in MM (Jiang Y., et al. 2020).
What is Cystatin C?
Cystatin C is a small protein found in the blood that acts as an inhibitor of cysteine proteases-enzymes that break down proteins. It's produced by almost all human cells and is filtered by the kidneys. Unlike other proteins in the blood, cystatin C levels are less affected by factors such as muscle mass, diet, or age, making it a reliable indicator of kidney function. Elevated levels of cystatin C can signal issues with kidney health, but its role extends beyond just kidney function.
Cystatin C and Myeloma Nephropathy
One of the most severe complications of multiple myeloma is kidney disease. The accumulation of abnormal monoclonal proteins and free light chains (FLCs) in the kidneys can lead to significant damage. FLCs, known for their nephrotoxic properties, primarily affect the proximal tubular epithelium, causing inflammation and fibrosis, and ultimately impairing kidney function. If left unchecked, this can lead to chronic kidney disease (CKD) or even kidney failure.
In the clinical setting, kidney function is traditionally assessed using markers like serum creatinine, which estimates the glomerular filtration rate (GFR). However, creatinine-based measurements can often underestimate kidney damage due to various interfering factors like muscle mass and certain medications. This is where cystatin C steps in as a game-changer.
Cystatin C offers a more reliable alternative for estimating GFR. It is freely filtered through the glomeruli and fully metabolized by the proximal tubular cells without being reabsorbed into the bloodstream or secreted by the renal tubules. The kidneys are the sole organs responsible for clearing cystatin C from circulation, making its levels a more accurate reflection of kidney function. Higher concentrations of cystatin C are directly correlated with reduced GFR, offering a more sensitive indicator of kidney damage in multiple myeloma patients.
Moreover, urinary cystatin C levels serve as a valuable clinical parameter for evaluating renal tubular function. Under normal conditions, cystatin C is reabsorbed and metabolized in the renal tubules. However, in patients with MM, tubular reabsorption can be disrupted due to fibrosis, leading to elevated levels of cystatin C in the urine. This makes cystatin C an excellent marker for early detection and monitoring of myeloma nephropathy.
Cystatin C with Myeloma Bone Disease
Bone disease is another major complication of multiple myeloma, presenting in about 80% of patients at diagnosis. This condition, known as myeloma bone disease (MBD), involves increased bone resorption due to heightened osteoclast activity and diminished bone formation due to osteoblast inhibition. The consequences include painful lytic lesions, fractures, and a marked reduction in quality of life.
The pathogenesis of MBD is complex, involving several signaling pathways. Key players include the receptor activator of nuclear factor-κB (RANK), its ligand RANKL, and osteoprotegerin (OPG), which together regulate osteoclast formation and activity. In multiple myeloma, the balance between RANKL and OPG is disrupted, leading to excessive bone resorption.
Interestingly, cystatin C has a dual role in MBD. On one hand, it can promote osteoclast differentiation and activation, exacerbating bone resorption. Cystatin C indirectly influences this process through the metabolism of homocysteine (Hcy), a sulfur-containing amino acid that enhances osteoclast activity via RANKL-independent pathways. Elevated Hcy levels can increase oxidative stress and disrupt bone matrix integrity, further contributing to bone disease. Research suggests that cystatin C inhibits the breakdown of Hcy, thereby increasing its concentration and promoting bone resorption.
On the other hand, cystatin C also exhibits protective effects against bone disease. It interferes with RANKL-induced osteoclast differentiation by inhibiting key transcription factors involved in osteoclast formation. Moreover, cystatin C negatively regulates the activity of cathepsin K, a cysteine protease with a high affinity for bone matrix proteins, which osteoclasts use to degrade bone. By inhibiting cathepsin K, cystatin C can reduce bone resorption. Additionally, studies indicate that cystatin C promotes osteoblast differentiation via the bone morphogenetic protein-2 (BMP-2) signaling pathway, enhancing bone formation and mineralization. This makes cystatin C a unique protein with both destructive and protective roles in bone health.
Clinical Implications and Prognostic Value
The overexpression of cystatin C in multiple myeloma links it not only to kidney and bone disease but also to tumor burden. Elevated cystatin C levels have shown a strong correlation with β2-microglobulin, a well-recognized indicator of tumor load and renal dysfunction in MM patients. This makes cystatin C a valuable marker for assessing tumor burden.
Furthermore, high serum cystatin C levels have been associated with advanced stages of multiple myeloma, making it a useful prognostic marker. Studies suggest that elevated cystatin C levels can predict poor overall survival (OS) and event-free survival (EFS). This helps clinicians categorize patients into different risk groups, guiding treatment decisions and improving patient outcomes.
Conclusion
Cystatin C is emerging as a multifaceted protein with significant implications for understanding and managing multiple myeloma. Its roles in kidney function, bone health, and disease prognosis make it a promising candidate for further study and clinical application. As research progresses, cystatin C may become an essential tool in the fight against multiple myeloma, offering new insights and therapeutic possibilities for patients battling this challenging disease.
References
- Jiang Y., et al. The role of cystatin C as a proteasome inhibitor in multiple myeloma. Hematology. 2020, 25 (1): 457-63.
- Finney H., et al. Serum cystatin C in patients with myeloma. Clinica Chimica Acta. 2001, 309 (1): 1-6.
- Nückel H., et al. Prognostic significance of serum cystatin C in multiple myeloma. International Journal of Hematology. 2012, 95: 545-50.
- Ferguson T. W., et al. Cystatin C as a biomarker for estimating glomerular filtration rate. Current opinion in nephrology and hypertension. 2015, 24 (3): 295-300.
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