Researchers have discovered a way to prevent kidney failure from occurring in people with multiple myeloma

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Multiple myeloma is a cancer of plasma cells.

Normal plasma cells are found in the bone marrow and are an important part of the immune system.

The immune system is made up of several types of cells that work together to fight infections and other diseases.

Lymphocytes (lymph cells) are one of the main types of white blood cells in the immune system and include T cells and B cells.

Lymphocytes are in many areas of the body, such as lymph nodes, the bone marrow, the intestines, and the bloodstream.

When B cells respond to an infection, they mature and change into plasma cells.

Plasma cells make the antibodies (also called immunoglobulins) that help the body attack and kill germs.

Plasma cells, are found mainly in the bone marrow.

Bone marrow is the soft tissue inside bones.

In addition to plasma cells, normal bone marrow is also the home for other blood cells such as red cells, white cells, and platelets.

In general, when plasma cells become cancerous and grow out of control, this is called multiple myeloma.

The plasma cells make an abnormal protein (antibody) known by several different names, including monoclonal immunoglobulin, monoclonal protein (M-protein), M-spike, or paraprotein.

There are, however, other plasma cell disorders that also have abnormal plasma cells but do not meet the criteria to be called active multiple myeloma.

These other plasma cell disorders include:

  • Monoclonal gammopathy of uncertain significance (MGUS)
  • Smoldering multiple myeloma (SMM)
  • Solitary plasmacytoma
  • Light chain amyloidosis.

Multiple myeloma features

Low blood counts

In multiple myeloma, the overgrowth of plasma cells in the bone marrow can crowd out normal blood-forming cells, leading to low blood counts.

  • This can cause anemia (a shortage of red blood cells). People with anemia become weak and fatigued.
  • Multiple myeloma can also cause the level of platelets in the blood to become low (called thrombocytopenia). This can lead to increased bleeding and bruising.
  • Another condition that can develop is leukopenia (a shortage of normal white blood cells). This can lead to problems fighting infections.

Bone and calcium problems

Myeloma cells also interfere with cells that help keep bones strong.

Bones are constantly being remade to keep them strong. Two kinds of bone cells work together to keep bones healthy and strong:

  • Osteoclasts break down old bone
  • Osteoblasts lay down new bone

Myeloma cells make a substance that tells the osteoclasts to speed up dissolving the bone.

So old bone is broken down without new bone to replace it, making the bones weak and easy to break.

Fractured bones are a major problem in people with myeloma.

This increase in bone break-down can also raise calcium levels in the blood. Problems caused by high calcium levels are discussed in Signs and Symptoms of Multiple Myeloma.

Infections

Abnormal plasma cells cannot protect the body from infections.

As mentioned before, normal plasma cells produce antibodies that attack germs.

In multiple myeloma, the myeloma cells crowd out the normal plasma cells, so that antibodies to fight the infection can’t be made.

The antibody made by the myeloma cells does not help fight infections.

That’s because the myeloma cells are just many copies of the same plasma cell – all making copies of the same exact (or monoclonal) antibody.

Kidney problems

Myeloma cells make an antibody that can harm the kidneys, leading to kidney damage and even kidney failure.

Researchers at the University of Alabama at Birmingham have discovered a way to prevent kidney failure from occurring in people with multiple myeloma.

Paul Sanders, M.D., a nephrologist in the Division of Nephrology at UAB, found that the development of chronic, progressive kidney damage can be prevented by blocking a pathway activated in the kidney by light chains proteins produced by cancer cells.

“In the process of catabolism by the kidney, certain monoclonal Ig light chains, FLCs, can promote significant changes in kidney epithelial cell biology,” Sanders said.

“In this paper, we demonstrated that monoclonal FLCs are biologically active proteins that can generate hydrogen peroxide in amounts sufficient to activate intracellular redox-sensitive signaling pathways in the proximal tubule.

We further identified a novel intracellular signal transduction mechanism that generated a pro-inflammatory and pro-fibrotic milieu in the kidney and featured Signal Transducer and Activator of Transcription 1, so-called STAT1.

To the extent that the experiments reflect the human condition, the studies offered new insights into the pathogenesis of progressive kidney failure that develops in the setting of multiple myeloma, which features increased circulating levels of monoclonal immunoglobulin fragments that require metabolism by the kidney.”

Nearly half of all patients who have multiple myeloma also have kidney injury, and approximately 8 percent of patients require renal replacement therapy.

This discovery will help slow down and prevent the development of kidney injuries in this patient population.

“Even with modern chemotherapeutic options and extracorporeal therapies designed to target the removal of monoclonal FLCs, reductions in circulating FLCs require time, permitting progression of kidney disease, which may occur rapidly with persistently elevated serum FLC levels,” Sanders explained.

“Targeting this pathway may prove beneficial in limiting the production of the FLCs and preventing the kidney injury that occurs from these proteins.”

The findings are novel, and it is the first time these results have been published.

“This work represents a logical extension of groundbreaking work from Dr. Sanders’ laboratory and demonstrates how the kidney is affected in multiple myeloma and the mechanisms by which light chains inflict kidney damage,” said Anupam Agarwal, M.D., director of the Division of Nephrology at UAB. “His laboratory first described the mechanism of ‘cast nephropathy’ in multiple myeloma and discovered a potential therapeutic intervention to prevent this complication.”

UAB researchers are currently working on developing molecules to block the pathway by which the light chains travel, which will eliminate kidney damage in people with multiple myeloma. Clinical trials will also be needed to demonstrate efficacy.

More information: Wei-Zhong Ying et al. Immunoglobulin light chains generate pro-inflammatory and pro-fibrotic kidney injury, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI125517
Journal information: Journal of Clinical Investigation
Provided by University of Alabama at Birmingham

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