What is Renal Disease in Monoclonal Gammopathies?
Kidney damage is a global health issue that’s increasing in frequency. It places a significant strain on the healthcare system and often results in poor outcomes for patients. Multiple myeloma, a disease that affects older people and represents about 10% of all blood-related cancers, is caused by the uncontrolled growth of abnormal plasma cells. These cells produce harmful proteins and cause damage to organs. Patients with multiple myeloma and similar conditions frequently have kidney problems due to a variety of associated diseases.
The kidney is often affected in patients with multiple myeloma and other diseases related to abnormal plasma cells. In fact, at the time of diagnosis, up to half of the patients have kidney damage, which is linked with a greater risk of death. Kidney failure is the second most frequent cause of death in patients with multiple myeloma, after infections.
Patients can experience a range of kidney damage, from mild and reversible acute kidney injury (a sudden episode of kidney failure or kidney damage that happens within a few hours or a few days) to severe damage that requires a treatment called hemodialysis (a procedure to remove waste and excess fluid from the blood when the kidneys can’t adequately do so). Some patients with multiple myeloma experience a slow worsening of kidney function over six months or longer. These patients are likely to have chronic kidney disease (long-term, progressive damage to the kidneys) and may eventually require hemodialysis.
Kidney disease related to abnormal plasma cell growth can be divided into two categories: those caused by immune proteins (immunoglobulins) and those not caused by immune proteins. However, there can be a lot of overlap between these two categories. Furthermore, the damage to the kidney can occur in various areas including the filters (glomeruli), tissue around the filters (tubulointerstitial), blood vessels, or a combination. Common aspects of the resulting kidney disease include acute kidney injury, chronic kidney disease, protein in the urine (proteinuria), blood in the urine (hematuria), specific crystal formation in the kidney (renal crystallopathy), and a disorder caused by the kidney’s failure to reabsorb nutrients (Fanconi syndrome).
The most common kidney disease linked to multiple myeloma is called “cast nephropathy,” found in 40% to 60% of kidney tissue samples from patients with multiple myeloma and kidney disease. The term “myeloma kidney” usually refers to this condition, but it is also seen in other disorders associated with an overload of proteins in the kidneys. It’s important to note that the presence of cast nephropathy doesn’t rule out other types of kidney disease related to the abnormal growth of plasma cells.
Other types of kidney disease associated with abnormal plasma cell growth include amyloidosis (a disease that occurs when a substance called amyloid builds up in your organs), conditions related to the deposit of immune proteins, types of kidney inflammation (glomerulonephritis), certain conditions involving clumps of immunoglobulins (immune proteins), and disorders involving crystal formation in the kidneys.
What Causes Renal Disease in Monoclonal Gammopathies?
Monoclonal gammopathies are a group of diseases where certain immune cells in the bone marrow multiply uncontrollably and deposit a type of protein known as immunoglobulin (Ig) in different tissues. This group of conditions includes multiple myeloma, Waldenstrom’s macroglobulinemia, conditions similar to multiple myeloma but less aggressive, certain types of leukemia and lymphoma. Despite having a lower amount of cancerous cells, which might not typically need treatment, these diseases might cause harm to the kidney, tilting the balance towards the need for treatment. Unfortunately, although treatments for myeloma have improved, recovery of kidney function is generally not very good in these patients.
Around 3% of adults aged 50 and above, and 5% of those aged 70 and above, have a type of protein called monoclonal protein (M-protein) present in their blood. If they do not fulfil the criteria for multiple myeloma such as having less than 3 g/dL of M-protein and having less than 10% of kidney cells being plasma cells (the cells involved in multiple myeloma), and not having damage to other organs, they are diagnosed with MGUS.
In 2012, a new category of kidney disorders was established, “monoclonal gammopathy of renal significance”, which includes patients who have renal impairment caused by monoclonal gammopathies, but who don’t fulfil the criteria for multiple myeloma or other related conditions. These patients usually benefit from treatment directed at reducing the level of M-protein. Excessive M-protein can also affect the nerves and the skin.
Typically, proteins are filtered by the kidney, and those that are too big or too small are not able to pass through. The proteins that do make it through are then processed and broken down into parts. However, if there’s too much protein, then the processes that deal with them might be overloaded, causing kidney damage. Furthermore, M-protein can also cause immune reactions that harm the kidneys.
One of the main features of monoclonal gammopathies is the overproduction of parts of the immunoglobulin, most often light chains by cancerous plasma cells. Normally, these light chains are created in larger quantities than heavy chains, and are processed by the kidney and broken down in the tubules. However, in these conditions, light chains that are produced by the cancerous cells are often not broken down. The unique features of each light or heavy chain can play a big role in what type of kidney damage happens. It’s also been found that not all light chains can cause damage to the kidneys, suggesting that some types might be more harmful than others.
The kidneys get injured due to the overproduction and the lack of breakdown of these light chains. Kidney injury caused by monoclonal gammopathies can be grouped into two categories: those caused by the immunoglobulins themselves and those that are not, although there is some overlap between these groups.
Risk Factors and Frequency for Renal Disease in Monoclonal Gammopathies
Multiple myeloma is a relatively rare type of cancer, making up about 1-2% of all cancer cases and around 17% of blood-related cancers. It tends to be more common in males and people of African-American descent. In the US, it’s estimated that about 7 out of 100,000 people are diagnosed with this condition each year. It often affects older individuals, with the average patient being diagnosed between the ages of 65 and 74. Very few people under the age of 40 get this disease. A small number of cases, about 3 in 1000, are thought to be inherited within families.
Depending on the exact case, anywhere from 20% to 50% of people with multiple myeloma can also have kidney failure at the time of diagnosis or later in their disease. This issue can significantly diminish a patient’s health outlook and raise their risk of dying.
- Multiple myeloma represents 1-2% of all cancers and about 17% of blood-related cancers.
- The disease is more common in males and people of African-American descent.
- Each year in the US, approximately 7 per 100,000 people are diagnosed with multiple myeloma.
- People are typically diagnosed between the ages of 65 and 74. Only 2% of patients are younger than 40 years.
- Family history contributes to a minor percentage of cases with an estimated 3 cases per 1000 patients with multiple myeloma.
- Between 20% and 50% of multiple myeloma patients may have kidney failure at diagnosis or during their illness.
- Multiple myeloma contributes to 1.5% of all cases of kidney replacement therapy.
- The 2-year mortality rate in patients with both end-stage kidney disease and multiple myeloma is 58%, compared to 31% in patients with just end-stage kidney disease.
Signs and Symptoms of Renal Disease in Monoclonal Gammopathies
Multiple myeloma, a type of cancer, can sometimes start with subtle signs like feeling generally unwell, feeling fatigued, losing weight, or experiencing bone pain. Chronic kidney disease (CKD) can also start this way. That’s why it’s important for healthcare providers to keep multiple myeloma in mind as a possible explanation when patients come in with these types of general symptoms.
Sometimes, multiple myeloma presents more dramatically, with patients suddenly experiencing severe acute kidney injury (which could require dialysis) or severe hypercalcemia (too much calcium in the blood) and dehydration. Another common symptom is anemia, which is found in about 75% of people with multiple myeloma. So if a patient has kidney problems and anemia, multiple myeloma could be a possibility.
Patients with specific forms of multiple myeloma, such as amyloidosis or MIDD, might experience systemic features like these:
- Gastrointestinal bleeding
- Heart failure
- An elevated level of a substance called alkaline phosphatase in the blood
- Cardiac arrhythmias (irregular heart rhythms)
- Periorbital purpura (purplish patches around the eyes).
In these cases, a simple blood pressure measurement can provide important clues. Patients with amyloid may have low blood pressure, possibly because of problems affecting the heart muscle and autonomic nervous system. In contrast, those with MIDD and kidney dysfunction usually have high blood pressure.
The first symptoms can be vague, like a lack of appetite, weight loss, bone pain, or signs related to kidney failure. Tests may show abnormal kidney function, worsening chronic kidney disease, high calcium levels in the blood, and anemia.
People with a condition known as light chain cast nephropathy commonly experience sudden kidney injury or worsening chronic kidney disease, along with protein in the urine.
The protein in the urine is usually made up of abnormal immune proteins called Bence Jones proteins or free light chains (FLCs). Patients with AL and MIDD can have systemic symptoms that include purpura, gastrointestinal bleeding, and heart problems that can lead to irregular heart rhythms or heart failure. These heart issues are more common in patients with AL. High blood pressure is typically seen in patients with cast nephropathy and MIDD due to kidney failure.
Testing for Renal Disease in Monoclonal Gammopathies
Previously, diagnosing a specific type of kidney disease called myeloma kidney involved multiple tests, including blood and urine tests as well as a kidney biopsy. However, recent advances in testing methods mean that kidney biopsies aren’t needed as often.
An international group of myeloma experts recommends two specific tests to evaluate this kidney condition: a 24-hour urine protein test and a blood test specifically for something called serum free light chains (sFLC). They recommend checking other factors as well, such as exposure to harmful substances, fluid balance, acid-base balance, urine test with microscopic exam, and blood calcium levels.
One thing to keep in mind is that a common blood test, called serum electrophoresis (SPEP), cannot always detect smaller amounts of M-protein – a protein related to myeloma. This is especially true if the M-protein is made up of free light chains, which don’t last as long in the blood as regular immunoglobulins. In fact, one study found that SPEP missed M-protein abnormalities in over half of the cases of AL amyloidosis.
In contrast to SPEP, serum-free light chain assays (sFLC) uses antibodies that are more sensitive to detecting such proteins. As such, international guidelines now recommend using sFLC, SPEP, and serum immunofixation tests instead of urinary tests because low-level M-protein might not be detected in urine until the kidney’s reabsorption capacity is exceeded.
The sFLC test measures the amounts of unbound kappa and lambda FLCs in the blood. The normal ratio of these two types of FLCs is between 0.26 and 1.65 in patients with healthy kidneys. In patients with kidney damage, this ratio can go as high as 3.1. High levels of these light chains and an abnormal ratio suggest a disorder related to monoclonal plasma cells. This test is generally more sensitive than the urine protein test for detecting FLCs and is helpful in diagnosing new cases and detecting disease relapses.
In patients with large amounts of FLCs, measuring urinary albumin – a protein usually found in the urine – can help distinguish between other types of kidney diseases related to monoclonal gammopathies, and could potentially avoid the need for a kidney biopsy. Usually, in diseases of the glomeruli – the filtering unit of the kidney – albumin is the main protein found in urine. However, in cast nephropathy, albumin usually makes up less than 10% of the urinary protein.
Kidney biopsies are considered safe for patients with multiple myeloma, but in some cases they can be avoided:
– If a patient with multiple myeloma has acute kidney injury and a high concentration of sFLC along with predominately monoclonal light chains in the urine, doctors can usually diagnose light chain cast nephropathy.
– If a patient has albuminuria or nephrotic syndrome – conditions characterized by high levels of albumin in the urine – along with a confirmed diagnosis of immunoglobulin light chain AL based on a biopsy from a non-kidney tissue, renal amyloidosis can typically be diagnosed.
– If a patient with either multiple myeloma or monoclonal gammopathy presents with symptoms consistent with Fanconi syndrome, light chain proximal tubulopathy can usually be diagnosed. Fanconi syndrome symptoms can include different types of urinary abnormalities, low blood phosphate, low blood potassium, low blood uric acid, and proteinuria.
Treatment Options for Renal Disease in Monoclonal Gammopathies
If you have kidney problems due to myeloma, a type of cancer that originates from plasma cells in your bone marrow, your doctors will first check how badly your kidneys are affected. They’ll also attempt to stabilize any imbalances in your body’s fluid and electrolyte levels. For example, they’ll make sure your body has the right amount of water, salts and minerals like sodium, potassium, calcium, and magnesium. Moreover, they will take steps to prevent further kidney damage by reducing the concentration of abnormal proteins or “casts”.
You might need to stop taking certain medications that can potentially harm your kidneys, such as anti-inflammatory painkillers, blood pressure medications called ACE inhibitors and ARBs, and certain types of contrast dye used for medical imaging. It’s important to stay well-hydrated, ideally producing around 3 liters (approximately 100 to 150 mL/hour) of urine a day. Depending on your condition, you might need to get fluids through an IV or by drinking. Yet, in cases with heart failure, fluid intake might need to be restricted.
In some situations, diuretics (water-pills) might be used to deal with excess water in your body, but they could potentially worsen your condition, so they’re used very carefully. In severe cases, you might need a treatment called hemodialysis which essentially does the job of the kidneys, ‘cleaning’ your blood of wastes and excess water and balancing its chemical composition. Hemodialysis could be especially helpful in managing symptoms caused by the buildup of waste products in the blood due to kidney impairment.
Also, your doctors may recommend starting chemotherapy with drugs such as bortezomib and dexamethasone as soon as possible. This treatment aims to reduce the levels of harmful proteins called free light chains (FLCs) in your body. Other treatments aiming to lower FLC levels, such as apheresis process (where blood is passed through a machine to remove the harmful proteins before being returned to the body), hemodialysis with special filters, and stem cell therapy (where your healthy stem cells are harvested, preserved, and then reintroduced after rigorous chemotherapy) might also be recommended.
Chemotherapy might involve different combinations of drugs including cyclophosphamide, bortezomib, dexamethasone, or lenalidomide among others. If successful, most patients will see an improvement in kidney function within three weeks of treatment. During this treatment, your blood levels will need to be closely monitored for a potentially dangerous condition known as tumor lysis syndrome, which can cause a sudden shift in the levels of certain substances in your blood.
If high levels of calcium are detected in your blood, your doctor may prescribe a group of drugs known as bisphosphonates. If your kidney function is significantly impaired, they may prefer a different drug, denosumab, over bisphosphonates. Some treatments, like the use of painkillers called NSAIDs, certain blood pressure medications, and certain types of contrast dye for imaging procedures should be avoided to prevent further harm to your kidneys.
In some cases, kidney or stem cell transplant might be an option. While this was traditionally not considered for patients with significant kidney problems, recent studies show that it might be a safe and effective option for some. The suitability for transplant is usually evaluated on an individual basis.
Finally, if the kidneys can no longer function on their own, a treatment called dialysis might be required. This treatment essentially mimics what healthy kidneys do: filter the waste, excess water and harmful substances from your blood. Special types of dialysis that use filters to remove harmful proteins from your blood could also be considered.
What else can Renal Disease in Monoclonal Gammopathies be?
People who have multiple myeloma, a type of cancer that forms in some types of white blood cells, might face issues with kidney function. There are various reasons why this can happen. So, when doctors try to find out why a myeloma patient is experiencing kidney impairment, they might consider different possible causes:
- Hypercalcemia causing a decrease in body fluid volume
- Hyperviscosity syndrome, where the blood gets too thick
- Tumor lysis syndrome, a dangerous complication that can occur during treatment for cancer
- POEMS syndrome, which stands for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes
What to expect with Renal Disease in Monoclonal Gammopathies
Patients with a type of cancer called myeloma, who also have significant kidney problems, generally have more challenging outcomes than those whose kidneys are functioning normally, regardless of intensive treatment. How well patients respond to chemotherapy (cancer-fighting drugs) plays a key role in determining their survival rates. For example, those who respond well to chemotherapy usually live an average of three years.
Recent studies involving patients with myeloma who need dialysis (a treatment that cleans the blood when the kidneys can’t) and don’t regain normal kidney function show survival rates of 50% at less than one year. However, this rate improves to 50% at three years for those who are able to stop dialysis. Data trends from 2001 to 2010 in the US show that the rate of end-stage kidney disease (when the kidneys no longer work and a transplant or dialysis is needed) caused by multiple myeloma may be decreasing.
Patients who have acute kidney injury (a sudden episode of kidney damage or failure) due to dehydration and high calcium levels in their blood usually recover better than those who have solidified protein clumps in their kidneys causing damage to the kidney’s tube-like structures. One study found that a larger amount of these protein clumps in the outer region of the kidney was linked to lower kidney function in follow-ups and a greater risk of needing ongoing dialysis.
The rising success rates can be attributed to more effective cancer drugs, such as thalidomide, lenalidomide, and bortezomib. The use of bortezomib, for example, has been reported to improve kidney function in 50% to 80% of patients newly diagnosed with myeloma.
Possible Complications When Diagnosed with Renal Disease in Monoclonal Gammopathies
Doctors caring for patients with myeloma kidney should be aware of the complications that can come with the disease. These include:
- Acute kidney injury, which is sudden damage to your kidneys
- Chronic kidney disease, a long-term condition where the kidneys don’t work as well as they should
- Hypercalcemia, a condition characterized by higher than normal calcium levels in the blood
- Hyperviscosity syndrome, a condition where the blood becomes thick
- End-stage renal disease (ESRD), a condition where the kidneys have stopped working
- Skeletal events like fractures
- Peripheral neuropathy, which is damage to the nerves outside your brain and spinal cord
Preventing Renal Disease in Monoclonal Gammopathies
Many people with multiple myeloma, a type of blood cancer, experience kidney failure. In fact, when first diagnosed, between 20% to 50% of those with multiple myeloma will have some degree of kidney failure. This can occur in different parts of the kidney, such as the glomerulus (the part of the kidney that filters blood), tubules (small tubes within the kidney), and interstitium (a network of tissue in the kidney).
Several tests, like serum-free light chains, serum electrophoresis, urine electrophoresis, and immunofixation should be done. These tests help doctors to better understand what’s happening in the body.
After a diagnosis, the first step in treatment is to evaluate how affected the kidneys are. After that, doctors will work towards adjusting the body’s hemodynamics (blood flow), volume status (fluid levels), and electrolyte disturbances (imbalances in body salts).
It’s crucial for patients to understand their condition. Regularly following the prescribed treatment strategy will improve their overall health outcomes. In other words, by sticking with the treatment plan provided by the doctor, patients can have a better chance at managing their condition.
