What are the other Names for this Condition? (Also known as/Synonyms)

• Amyloidosis due to Dialysis
• B2M Amyloidosis
• Dialysis-Related Beta2-Microglobulin Amyloidosis

What is Dialysis-Related Amyloidosis? (Definition/Background Information)

• Amyloidosis is a group of disorders in which the ‘amyloid protein’ builds up in many organs and tissues of the body. The term “amyloid” is used for protein molecules of any type that stick together owing to misfolding (or incorrect formation of the proteins)
• These protein aggregates are abnormally-formed and arranged into fibrils (slender fibers). An amyloid build-up can occur locally in only one organ, or may occur throughout the body 
• Dialysis-Related Amyloidosis (DRA) occurs in individuals who have undergone dialysis for several years. Prolonged hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) can both lead to DRA
• The underlying cause is kidney failure. In such patients, dialysis is not capable of effectively removing the beta-2-microglobulin (B2M) protein that is present on white blood cells and in body fluids
• The B2M protein begins accumulating in blood and gets deposited in the tendons and joints, causing stiffness and pain. There is no cure for Dialysis-Related Amyloidosis; although, kidney transplantation may alleviate the symptoms and delay progression of the condition

Who gets Dialysis-Related Amyloidosis? (Age and Sex Distribution)

• Dialysis-Related Amyloidosis occurs in individuals undergoing long-term hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)
• Although any individual on prolonged dialysis is vulnerable, those over the age of 60 are more likely to be affected
• The exact prevalence of DRA is not clear. It is believed that long-term dialysis, for periods over 4 years or even longer, may lead to this condition
• Both men and women on dialysis are equally susceptible to this condition

What are the Risk Factors for Dialysis-Related Amyloidosis? (Predisposing Factors)

• Individuals on long-term dialysis (that includes both hemodialysis and continuous ambulatory peritoneal dialysis) are at a high risk for Dialysis-Related Amyloidosis 
• Adults over the age of 60 years undergoing dialysis for prolonged periods are at a much higher risk for DRA

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dialysis-Related Amyloidosis? (Etiology)

Dialysis-Related Amyloidosis is caused by kidney failure and subsequent long-term dialysis administration.

• Dialysis is not capable of effectively removing a protein called beta-2-microglobulin (B2M) 
  • Normally, the B2M protein is present on the surface of white blood cells, as well as in several body fluids (including blood, cerebrospinal fluid, and urine) 
  • Under conditions where white blood cells increase (such as infection or inflammation), there is a concomitant increase in the levels of B2M
  • Additionally, prolonged disease and damage to kidneys can also result in elevated B2M levels
• The excess B2M proteins undergo misfolding, form aggregates and fibrils, and begin circulating in the bloodstream
• Subsequently, these abnormal amyloid proteins get deposited in the tissues and organs resulting  in the characteristic symptoms of Dialysis-Related Amyloidosis
• In DRA, most deposits occur in the osteoarticular system, which involves the bones, muscles, tendons, ligaments, and synovial membranes

The non-clearance of beta-2-microglobulin causes Dialysis-Related Amyloidosis. However, not all individuals who undergo long-term dialysis develop DRA. Therefore, it is theorized that certain additional factors may be involved in the development of DRA.

What are the Signs and Symptoms of Dialysis-Related Amyloidosis?

The signs and symptoms of Dialysis-Related Amyloidosis may vary in type and severity among affected individuals. The condition typically affects the bones, muscles, ligaments, tendons, and certain membranes called synovium (connective tissue that lines the inside of bones and ligaments).

The signs and symptoms of DRA may include:

• Weakness
• Pain in joints
• Joint stiffness
• Fluid accumulation in the joints
• Swelling of the joints
• Formation of bone cysts, leading to fragile bones
• Bone fractures
• Carpal tunnel syndrome, where the wrists are affected, causing:
  • Numbness
  • Tingling sensations
  • Muscle weakness in hands
• Tears in tendons and ligaments, causing pain

In addition, the following organs and tissues may also be involved and affected in DRA, resulting in a set of associated signs and symptoms:

Signs and symptoms related to the heart:

• Anemia
• Fatigue
• Decreased urine output; increased urge to urinate at night time
• Shortness of breath with physical exertion or while lying down
• Irregular heartbeats
• Chest pain
• Enlargement of heart; fluid build-up around the heart
• Excess cholesterol in blood
• Unintended weight loss
• Edema, or swelling, in abdomen, hands, feet, legs and face

Signs and symptoms related to the respiratory tract:

• Hoarseness in voice
• Cough, which may contain blood
• Wheezing
• Grating noise while breathing (stridor)
• Labored breathing, which may mimic asthma symptoms
• Shortness of breath
• Repetitive infections in the respiratory tract, which may mead to pneumonia
• Night sweats

Signs and symptoms related to the gastrointestinal system:

• Thickening of tongue (macroglossia)
• Acid reflux (gastroesophageal reflux disease or GERD)
• Sluggish peristaltic movement (process that moves food in the GI tract by involuntary muscle contractions)
• Nausea
• Loss of appetite; feeling of fullness after eating a small amount of food
• Gastric polyps (nodules on the stomach wall)
• Slowing of stomach emptying (gastrointestinal atony) 
• Pseudo-obstruction of intestines; a sense of blocked intestines without any actual physical blockage
• Abdominal bloating and distension; abdominal pain
• Constipation or diarrhea that may even contain blood
• Clay-colored stools; or, fatty and foul-smelling stools (steatorrhea)

How is Dialysis-Related Amyloidosis Diagnosed?

Dialysis-Related Amyloidosis is diagnosed on the basis of the following tests and exams:

• A thorough physical examination
• Evaluation of personal and family medical history
• Assessment of the presenting signs and symptoms
• Blood tests: 
  • For complete blood count (CBC)
  • To assess abnormal antibodies 
  • To check heart function (cardiac biomarkers for stress on the heart)
  • To check kidney function
  • For measuring amyloid proteins
• Urine tests to check for excess protein (a 24 hour urine test is usually performed)
• Electrocardiography and echocardiography for checking heart functions
• Imaging tests, to assess amyloid deposits in the body/organs, and to assess damage to the organs, tissues, and bones, which include:
  • X-rays
  • Ultrasound imaging
  • Computed tomography scanning
  • Magnetic resonance imaging
  • Serum amyloid protein (SAP) scintigraphy scan: In this procedure, a small amount of radiolabeled (radioactive iodine) SAP is introduced through injection into the body. After several hours, individuals are scanned with a whole body gamma scanner to check for amyloid deposits in the tissues and organs. Individuals undergoing this procedure ingest potassium iodide before and after the procedure, to prevent the thyroid glands from absorbing the radioactive iodine
• Tissue biopsy: A biopsy of an affected organ or tissue is performed and sent to a laboratory for a pathological examination. A pathologist examines the biopsy sample under a microscope. After putting together clinical findings, special studies on tissues (if needed) and with microscope findings, the pathologist arrives at a definitive diagnosis. Examination of the biopsy sample under a microscope by a pathologist is considered to be gold standard in arriving at a conclusive diagnosis. In case of Dialysis-Related Amyloidosis,
  • Biopsy of tissue from affected organ or tissue may be necessary
  • Amyloid deposit from affected tissue is detected using a staining procedure. When stained with Congo red stain, the amyloid protein deposits appear green under a special type of microscope (polarizing microscope)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Dialysis-Related Amyloidosis?

The potential complications of Dialysis-Related Amyloidosis include:

• Stiffness and pain in joints leading to difficulty with movement
• Dizziness and risk of fall, if one stands up too quickly from a seated position
• Increased risk of fractures
• Heart failure

How is Dialysis-Related Amyloidosis Treated?

Currently, there is no cure for Dialysis-Related Amyloidosis. The treatment methods are tailored towards offering relief from symptoms and delaying progression of the condition. The following are some treatment modalities for DRA:

• Diet: Having frequent and small meals through the day, with reduced fat and sodium content
• Medication for pain, which may include analgesics, non-steroidal anti-inflammatory drugs, and steroids
• Chemotherapy may be used to destroy abnormal cells producing amyloid proteins. The chemotherapeutic drugs may be combined with dexamethasone or prednisone
  • Cyclophosphamide
  • Melphalan
• Use of lixelle beta 2-microglobulin apheresis column for dialysis-induced Amyloidosis. This device removes beta-2 microglobulin from blood
• Better filters for dialysis machines (such as biocompatible high-flux membranes for individuals on hemodialysis)
• Surgery to repair tears in tendons and ligaments, as well as to remove bone cysts
• Kidney transplantation to help delay progression of DRA
• Pacemaker implantation to improve heart function
• Heart transplantation for severe dysfunction of heart

How can Dialysis-Related Amyloidosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Dialysis-Related Amyloidosis
• Use of better filters for dialysis may help delay progression of DRA
• Active research is currently being performed to explore the possibilities for treatment and prevention of acquired disorders such as DRA
• Regular medical screening at periodic intervals with tests and physical examinations are highly recommended

What is the Prognosis of Dialysis-Related Amyloidosis? (Outcomes/Resolutions)

• The prognosis of Dialysis-Related Amyloidosis is determined by the period (number of years) one has undergone dialysis, the extent of damage to major organs, and the overall health of the affected individual
• Kidney transplantation may help in delaying progression of DRA. However, the damage to organs and tissues that has taken place, is not reversible
• If a major organ, such as the heart, is affected, the prognosis is particularly guarded

Additional and Relevant Useful Information for Dialysis-Related Amyloidosis:

• Approximately, 30 different proteins with a tendency to form amyloids have been identified. These are known as precursor proteins or amyloidogenic proteins
• The misfolding of proteins can occur due to a number of reasons, including aberrant formation, improper breakdown, or accumulation beyond a critical concentration in serum