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How Does Multiple Myeloma Cause Kidney Failure

Outcomes Of Patients With Ndmm Requiring Dialysis2

Is there a link between MGUS and kidney damage in myeloma patients?

A single-center study analyzed the outcomes of patients with newly diagnosed MM requiring dialysis. The median age of the patients was 69 years, and 100% of patients had renal disease International Staging System Stage 3. The 82% of patients received bortezomib -based treatment:

  • 21% V plus dexamethasone
  • 44% V plus cyclophosphamide and d
  • 15% V plus thalidomide and d
  • 2% PS-341/bortezomib plus doxorubicin and d

Renal responses were observed in the 50% of patients, and dialysis independence in 49% of V-treated patients. The MM response was:

  • Overall response rate: 64%
  • Very good partial response: 32%
  • Partial response: 26%

Achieving a partial response in the first 2 months was associated with a higher probability of renal responses . Responders were able to discontinue dialysis and benefit of a better overall survival .

Table 1. Regimens frequently used to manage MM related AKI in frontline setting4

In conclusion, acute renal insufficiency is a myeloma emergency, and rapid diagnosis and management is the key to survival and renal recovery. In patients requiring dialysis, a rapid response to V-based treatments is associated with higher probability of renal recovery and independence from dialysis. Consequently, V-based treatments remain the standard of care for the management of myeloma-related renal impairment, but further improvement is needed in this patient population to improve general outcomes and renal recovery rates.

Patients And Study Design

The / FLC ratio in serum and eGFR was analyzed retrospectively by Chronic Kidney Disease Epidemiology Collaboration equation in 1469 consecutive patients attended in Hospital Clínic of Barcelona between December 2014 and December 2017. Data were retrospectively obtained regarding sFLC, sFLC ratio, renal function , CKD stage and chain isotypes in the active MM group. Two groups were selected: a control group comprising patients with no haemathological disorders including no presence of monoclonal gammopathy of undetermined significance by immunofixation or MM with CR and a group with diagnosis of active MM . Patients diagnosed of MGUS or other hematological diseases were excluded. Only patients with stable renal function in the last 3months were included.

Clinical Impact Of Kidney Dysfunction In Multiple Myeloma

International Myeloma Working Group definition of multiple myeloma . *MM-related organ damage includes the following: hypercalcemia renal insufficiency anemia bone, lytic lesions, or osteoporosis with compression fracture and symptomatic hyperviscosity, amyloidosis, or recurrent bacterial infections . BMPC = bone marrow plasma cells.

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How Did I Get It

Multiple myeloma is a type of blood cancer and we do not know exactly why people get it. It is a rare disease and affects only about 1 in 4,000 people. Each year about 13,000-20,000 people will be diagnosed with this disease.

There are some studies that show people who have been exposed to certain toxins like radiation, benzene, herbicides, insecticides, and organic solvents are more at risk than the general population. However, many people develop multiple myeloma without any exposure to these agents. Typically the age at which people are most likely to be diagnosed with multiple myeloma is in their 50s and 60s.

We often do not know why people develop this disease and it is not possible to predict who will develop it. In order to get myeloma kidney, you must have multiple myeloma.

Not all patients with multiple myeloma will develop myeloma kidney, generally about 30-50% of patients develop this problem. There are things that will make a patient with multiple myeloma more at risk to develop myeloma kidney. Dehydration, therapy with furosemide , high blood levels of calcium, and high levels of sodium in the urine all can lead to increased formation of these casts.

Why Does Multiple Myeloma Cause Kidney Failure

PPT

Though considered a rare disease, multiple myeloma is the second-most common type of blood cancer and is diagnosed in about 32,000 people a year in the U.S. While its origins are still unknown, the disease affects plasma cells, a specific type of white blood cell.

Many patients battling multiple myeloma also suffer concerning complications, several of which can contribute to impaired kidney function. Up to 85% of myeloma patients experience this malfunction, which often is caused by the disease itself.

The myeloma cells produce incomplete antibodies, also called light chains, says Jens Hillengass, MD, PhD, Chief of Myeloma at Roswell Park Comprehensive Cancer Center. These abnormal proteins, excreted through the kidneys, can cause damage to the kidney tissue with blockage, inflammation and fibrosis. In rare cases, the proteins are deposited as so-called amyloid fibrils, which are harmful protein fragments, leading to a condition known as amyloidosis.

Joined together, the abnormal and normal proteins become too large to pass through the kidneys filters, called glomeruli, which are clusters of capillaries around the end of kidney tubules. They obstruct the passages, preventing fluid from passing through the kidneys. This causes inflammation in the kidney tissue, leading to kidney damage, according to Dr. Hillengass.

The resulting damage leads to a condition called cast nephropathy, or myeloma kidney, which occurs in 20% of multiple myeloma patients.

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Chronic Kidney Disease In Multiple Myeloma

There is an even higher prevalence of the earlier stages of CKD, with adverse outcomes, including loss of kidney function, cardiovascular disease , and premature death. The KDIGO organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of CKD . Diagnostic thresholds of GFR of less than 60mL/min/1.73m2 and an albumin-creatinine ratio of 30mg/g or greater were retained. The exact frequency of GFR and ACR monitoring will depend on the severity of CKD Figure 3 and the risk and rate of progression. The International Myeloma Working Group has recommended the use of the Modification of Diet in Renal Disease formula for the estimation of GFR in MM patients with stabilized sCr as well as the KDIGO classification for the classification of CKD in MM .

Guide to frequency of monitoring by GFR and albuminuria categories . This GFR and albuminuria grid reflects the risk for progression by intensity. The numbers in the boxes are a guide to the frequency of monitoring . ACR = albumin creatinine ratio CKD = chronic kidney disease GFR = glomerular filtration rate.

What Is Myeloma Kidney

Kidney failure is a common complication of multiple myeloma. When first diagnosed, as many as 20-40% of patients with multiple myeloma will have some amount of kidney failure. Multiple myeloma can affect the kidney in several ways. It can affect the filter , the tubules , or the tissue of the kidney itself . The effect of multiple myeloma on the glomerulus due to light chain, heavy chain deposition, and amyloidosis will be reviewed on this web site under those specific topics. This page is going to focus on the affect of multiple myeloma on the tubules of the kidney, commonly referred to as myeloma kidney. It is also known as cast nephropathy.

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Breathing Problems And Multiple Myeloma

Shortness of breath, also called dyspnea, is a common symptom of multiple myeloma, a type of cancer that forms in blood cells.

Feeling like you cant catch your breath or, in severe cases, feeling like you cant breathe at all can be extremely worrying. Fortunately, there are things you can do to ease this symptom of multiple myeloma and the anxiety and fear that it causes.

How Do Crab Symptoms Influence Treatment

How does myeloma affect the kidneys? What causes kidney problems in myeloma?

Doctors can use the CRAB symptoms to differentiate between active multiple myeloma and MGUS.

MGUS needs to be actively monitored with regular blood tests but doesnt require treatment. Your doctor may recommend taking medications to increase your bone density.

Multiple myeloma is diagnosed if at least one CRAB symptom or specific biomarkers develops:

  • the clonal bone marrow plasma cells are greater than 60 percent
  • the serum free light chain ratio is greater than 100 mg/L
  • more than one focal lesion on an MRI scan

Many people with myeloma show abnormalities in lab blood tests before they develop symptoms.

Multiple myeloma requires active treatment if one or more CRAB symptom develops. Treatment usually consists of medications to destroy cancer cells and treat specific symptoms. People in otherwise good health may also be candidates for bone transplants.

In the United States, the most common initial therapy for people eligible for bone transplants is a combination of the medications:

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The Effect Of Diet On The Survival Of Patients With Chronic Kidney Disease

Individuals with CKD should introduce appropriate measures to hamper the progression of kidney function deterioration as well as prevent the development or progression of CKD-related diseases.

A kidney-friendly diet may help to protect kidneys from further damage. Patients with kidney damage should limit the intake of certain foods to reduce the accumulation of unexcreted metabolic products and also to protect against

  • hypertension,
  • proteinuria and
  • other heart and bone health problems

A recent systemic study revealed that a healthy diet comprising many fruits and vegetables, fish, legumes, whole grains, and fibers and also the cutting down on red meat, sodium, and refined sugar intake was associated with lower mortality in people with kidney disease

A kidney-friendly diet may help to protect kidneys from further damage. In early CKD stages the adoption of healthy diet might slow glomerular filtration rate decline and decrease the prevalence of complete kidney failure . Patients with kidney damage should limit the intake of certain foods to reduce the accumulation of unexcreted metabolic products but also to protect against hypertension, proteinuria and other heart and bone health problems

Appropriate nutrition is vital for patients with CKD at all stages. Numerous studies indicate that diet rich in fruits, vegetables, fish, cereals, whole grains, fibers and polyunsaturated fatty acids but low in saturated fatty acids is beneficial for CKD patients

How Is It Diagnosed

In order to diagnose myeloma kidney, a biopsy needs to be done. However, there are other tests that need to be done to diagnose multiple myeloma. These include blood tests, urine tests, x-rays of the bones, and a bone marrow biopsy. The blood tests and urine tests can detect the abnormal proteins that are made by the plasma cells. The x-rays of the bones look for lesions in the bones caused by the multiple myeloma. The bone marrow biopsy will find the abnormal plasma cells inside the bones.

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What Are The Symptoms

The symptoms of multiple myeloma are typically fatigue, bone pain, and infections. This is because multiple myeloma causes anemia, destruction of the bones, and decreased production of normal antibodies that fight infection. The destruction of the bones due to multiple myeloma can often lead to fractures of the bone that occur with little or sometimes no trauma. Often, though, the signs of kidney dysfunction will be first discovered on lab work done for another medical reason.

Lab results could show increased level of creatinine, or increased amount of protein in the urine. People who develop advanced kidney disease will have symptoms related to kidney failure including nausea, itching, confusion, and fatigue.

Innovative Strategies To Combat Kidney Disease

PPT

High blood pressure, elevated blood sugar¸ NSAIDs , certain medications, and high-protein diets are the most common threats to kidney health. The potentially lethal insults they inflict include oxidative stress, production of advanced glycation and lipoxidation end products , inflammation, and an excessive filtration burden that taxes renal function over time.

Nutrients such as pyridoxal-5-phosphate fight AGEs and ALEs. CoQ10, silymarin, resveratrol, and lipoic acid are also clinically supported, potent interventions. Omega-3 fatty acids help quell inflammation, contributing to enhanced kidney health. A host of additional nutrients complement these actions, including folic acid and vitamins C and E.

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What Does It Look Like

To determine why the kidney is failing we often need to get a biopsy of the kidney to look up close at the glomeruli and the tubules. When someone has cast myeloma kidney, you can see the tubules full of proteins that blocks the inside of the tubule.

The glomeruli of the kidney are typically not affected in cast nephropathy and usually appear normal.

The Relationship Between Renal Function And Survival In Mm

An early Medical Research Council myelomatosis trial reported a higher number of deaths within 100 days of recruitment in patients with a serum urea 15 µmol/l, or creatinine 200 µmol/l if the urea was < 15 µmol/l, at diagnosis. Patients presenting with RI had an OS of 380 days with 28% survival at 2 years, compared to 52% for the entire study population at the same time point . RI was responsible for 28% of the early deaths in a subsequent analysis that combined data from the MRC IV to MRC VIII trials that excluded a large proportion of patients presenting with severe AKI . A total of 3,107 patients from the MRC myelomatosis trials between 1980 and 2002 were eligible to participate in this study.

A recent retrospective study from 15 Swedish hospitals reported a significantly inferior OS in patients with RI compared to those who did not have RI. The survival of patients with RI who were treated with bortezomib-based chemotherapy was better than survival of those who received conventional agents . Mayo Clinic investigators reported a complete renal response rate in a higher proportion of patients treated with novel agents compared to conventional treatment. Improvement of renal function was associated with better OS, although still inferior to patients with no RI at diagnosis .

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Is There A Link Between Multiple Myeloma And Kidney Failure

Multiple myeloma is a rare type of cancer of the blood. Myeloma affects the plasma cells in the blood, which are responsible for fighting off infections, thus making the body more susceptible to all types of infectious diseases. As the cancerous cells of multiple myeloma grow and spread throughout the body, they start causing bone damage at different places along with several health complications. One of the most affected organs by multiple myeloma, other than bones and blood, are your kidneys. Kidney failure is known to be a common complication of multiple myeloma. So, is there really a link between multiple myeloma and kidney failure? And if so, what is this connection that causes your kidneys to fail? Read on to know more.

What Is The Treatment

Myeloma Kidney Disease

The treatment for the kidney disease associated with multiple myeloma depends upon treating the myeloma itself. Patients with multiple myeloma are treated with chemotherapy and/or bone marrow transplant. Bone marrow transplant is only for patients who have good mobility and function and do not have severe kidney, liver, or heart disease. For chemotherapy, the most common regimen involves a combination of prednisone, thalidomide, and melphalan. Chemotherapy can help reduce the production of the abnormal proteins by the plasma cells, which is very important for patients with myeloma kidney. By reducing the abnormal protein in the blood, the kidney will have a chance to recover.

In addition to chemotherapy to treat the multiple myeloma, there are a few other things that can help patients with myeloma kidney. Keeping hydrated is very important, because being dehydrated can lead to more cast formation. Therefore, drinking 2-3L of water a day is recommended. Avoiding NSAIDs and diuretics are important because these medications cause more cast formation. Treating high blood levels of calcium is important so that the high calcium levels do not filter through the kidney and make cast formation worse. High calcium levels are usually treated with medications such as pamidronate and zolendronic acid. Finally, patients with multiple myeloma and especially those with myeloma kidney should not get IV contrast.

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Autologous Stem Cell Transplantation

High-dose chemotherapy followed by ASCT is an established treatment option for MM. RI had no impact on stem cell collection and post-transplant engraftment in small single-centre studies , with some centres reporting cases of recovery from requiring dialysis .

High-dose melphalan is associated with excessive toxicity when the dose of melphalan was reduced to 140 mg/m2 in a study where 21 of the 81 patients had advanced RI , transplant-related mortality was observed in 6 and 13% of patients after single and tandem ASCT, respectively. Dialysis dependence and melphalan dose did not affect event-free survival or OS . In a subsequent study in dialysis patients, a further reduction in melphalan dose produced a similar toxicity profile, transplant-related mortality, disease response and OS compared to patients with no RI .

More recently, Mayo clinic investigators reported long-term outcomes following ASCT in 30 patients with advanced RI 15 patients were receiving dialysis, and only 1 recovered renal function. The non-dialysis patients had a modest improvement in eGFR from 15 to 19 ml/min. CR was noted in 14 patients. Although patients who achieved a CR had a better median eGFR than those who did not, the authors found no association between haematological response and baseline eGFR with renal outcome .

Pathogenesis Of Renal Failure In Multiple Myeloma: Any Role Of Contrast Media

Giampaolo Merlini

1Laboratory Medicine Service, IRCCS AOU San Martino-IST, National Institute for Cancer Research, University-Hospital San Martino, Largo Rosanna Benzi 10, 16132 Genova, Italy

2Amyloidosis Research and Treatment Center, Clinical Chemistry Laboratories, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy

3Department of Molecular Medicine, University of Pavia, Italy

Abstract

1. Introduction

2. Kidney Diseases Associated with Plasma Cells Dyscrasias

Common
Light-chain cast nephropathy
Immunoglobulin-related amyloidosis
Monoclonal immunoglobulin deposition disease
Acute tubular necrosis
Drugs
Intravascular iodinated contrast
Type I and type II cryoglobulinemic glomerulonephritis
Uncommon
Light chain proximal tubulopathy
Crystal-storing histiocytosis
Nonamyloid monoclonal fibrillary glomerulonephritis
Immunotactoid glomerulonephritis/glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits
C3 glomerulonephritis associated with monoclonal gammopathy
Proliferative glomerulonephritis with monoclonal Ig deposits
Hyperviscosity syndrome
IgM, IgA, and rarely IgG myeloma
Plasma cell infiltration

3. Pathogenesis of Kidney Failure in Malignant Plasma Cells Dyscrasias

4. Mechanisms of Free Light Chains Nephrotoxicity

5. Risk Factors and Correlated Mechanisms Precipitating Kidney Failure

10. Conclusions

Conflict of Interests

Acknowledgments

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