DIAGNOSIS AND TREATMENT OF RARE GENETIC AND AUTOIMMUNE KIDNEY CONDITIONS COMMON AND UNCOMMON KIDNEY DISEASES
JASSIN M. JOURIA, MD
Dr. Jassin M. Jouria is a practicing Emergency Medicine physician, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serve as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.
Abstract
The kidneys serve as the body’s filtration system. Waste and excess fluids are filtered out of the blood and excreted through the urine. When the kidneys are not working as they should, fluid, electrolytes, and wastes can build up to dangerous levels in the body, even to the point of being fatal. Because kidney disease often does not create noticeable symptoms until the disease is advanced, it is important that medical clinicians are able to recognize the symptoms as soon as they are present and take immediate steps to resolve or mitigate the impact.
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This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 3 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.
Pharmacology hours include .5 hours (30 minutes).
Statement of Learning Need
Clinicians need to understand the symptoms of the varied stages of kidney disease and the types of blood or urine laboratory testing that are available to detect abnormalities indicating early stages of kidney disease in order to take immediate steps to resolve or mitigate serious health outcomes.
Course Purpose
To provide health clinicians with knowledge about the varied types of kidney disease, as well as diagnostic methods to achieve early recognition of and to initiate and effectively treat kidney disease.
2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.
3 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. The primary sign of ______is the appearance of blood in the urine (hematuria) early in life.
a. Alport syndrome b. amyloidosis c. Goodpasture syndrome d. Wegener granulomatosis
2. The most common form of Alport syndrome is
a. autosomal recessive Alport syndrome (ARAS) b. autosomal dominant form (ADAS) c. primary Goodpasture syndrome d. X-linked Alport syndrome (XLAS)
3. The cause of ______is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody).
a. Alport syndrome b. Wegener granulomatosis c. primary amyloidosis (AL) d. Goodpasture syndrome
4. The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the
a. COL4A5 gene. b. aggregation-prone serum protein. c. transthyretin gene. d. HLA-DPB1 gene.
5. True or False: By age 60, nearly 100% of untreated males with X- linked Alport syndrome (XLAS) develop kidney failure.
a. True b. False
4 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Introduction
There are many genetic diseases that directly or indirectly affect the kidneys. Some inherited kidney conditions are relatively common, while others are rare syndromes. Inherited kidney conditions are often associated with multisystem complications, complicating the course of care for many patients and adversely affecting quality of life. Health problems associated with these conditions range from mild to severe. As these conditions progress, patients can continue to live productively for many years. Inherited kidney conditions are challenging to treat. Clinical studies and research identify new inherited kidney diseases and target treatments for them. Inherited kidney conditions discussed in this article are Alport syndrome, amyloidosis, Goodpasture syndrome, and granulomatosis with polyangiitis.
Alport Syndrome
Alport syndrome is a rare genetic disorder characterized by progressive kidney disease and abnormalities of the ears and eyes. There are three genetic types. X-linked Alport syndrome (XLAS) is the most common; in these families affected males typically have more severe disease than affected females. In autosomal recessive Alport syndrome (ARAS) the severity of disease in affected males and females is similar. There is also an autosomal dominant form (ADAS) that affects males and females with equal severity.
The hallmark of the disease is the appearance of blood in the urine (hematuria) early in life, with progressive decline in kidney function (kidney insufficiency) that ultimately results in kidney failure, especially in affected males. About 50% of untreated males with XLAS develop kidney failure by
5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com age 25, increasing to 90% by age 40 and nearly 100% by age 60. Females with XLAS usually do not develop kidney insufficiency until later in life. They may not develop kidney insufficiency or failure at all, but the risk increases as they grow older. Both males and females with ARAS develop kidney failure, often in the teen-age years or early adulthood. ADAS tends to be a slowly progressive disorder in which renal insufficiency does not develop until well into adulthood.
Individuals with Alport syndrome can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision. XLAS is caused by mutations in the COL4A5 gene. ARAS is caused by mutations in both copies of either the COL4A3 or the COL4A4 gene. ADAS caused by mutations in one copy of the COL4A3 or COL4A4 gene. Alport syndrome is treated symptomatically and certain medications can potentially delay the progression of kidney disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required.133,134
Signs and Symptoms
The onset, symptoms, progression, and severity of Alport syndrome can vary greatly from one person to another due, in part, to the specific subtype and gene mutation present. Some individuals may have a mild, slowly progressive form of the disorder, while others may have earlier onset of severe complications.
The first sign of kidney disease is blood in the urine (hematuria). Hematuria is usually not visible to the naked eye, but can be seen when the urine is examined under a microscope. This is referred to as microscopic hematuria. Sometimes, blood may be visible in the urine (i.e., the urine may be brown,
6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com pink, or red) for a few days, usually when an affected individual has a cold or the flu. This is referred to as an episode of gross hematuria. Males with XLAS usually develop persistent microscopic hematuria early in life. About 95% of females with XLAS syndrome exhibit microscopic hematuria, but it may come and go (intermittently). Both males and females with ARAS develop hematuria during childhood. Males and females with ADAS also have hematuria.135,136
With time, many affected individuals exhibit elevated levels of albumin and other proteins in the urine (albuminuria and proteinuria), which are indications that kidney disease is progressing. The next stage in progression is gradual loss of kidney function, frequently associated with high blood pressure (hypertension), until, ultimately, the kidneys fail to work (end stage renal disease (ESRD). The kidneys have several functions including filtering and excreting waste products from the blood and body, creating certain hormones, and helping to maintain the balance of certain minerals in the body such as potassium, sodium, chloride, and other electrolytes. A variety of symptoms can be associated with ESRD including weakness and fatigue, changes in appetite, puffiness or swelling (edema), poor digestion, excessive thirst and frequent urination.137
As noted above, the rate of progression of kidney disease varies greatly. Many males with XLAS develop ERSD by their teenage years or early adulthood, although some will not develop kidney failure until their 40s or 50s. Most females with XLAS do not develop kidney insufficiency until later in life. Kidney failure is less common than in males with XLAS – about 15% by age 45 and 20-30% by age 60.138
7 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Progressive hearing loss (sensorineural deafness) occurs frequently in people with Alport syndrome. Sensorineural deafness results from impaired transmission of sound input from the inner ears (cochleae) to the brain via the auditory nerves. The hearing loss is bilateral, meaning it affects both ears. Diminished hearing is usually evident by late childhood in males with XLAS although it may be mild or subtle. In males with XLAS the frequency of hearing loss is approximately 50% by age 15, 75% by age 20 and 90% by age 40.
Hearing loss is progressive and may require hearing aids as early as the teenage years. Hearing aids are typically very helpful in people with deafness due to Alport syndrome. The onset, progression and severity of hearing loss in Alport syndrome varies greatly due to, in part, the specific genetic mutation present in each individual. Hearing loss in females with XLAS occurs less frequently than in males and usually occurs later in life, although a smaller percentage of females will develop hearing loss in their teenage years. Both males and females with ARAS develop hearing loss, usually during late childhood or early adolescence. Individuals with ADAS may develop hearing loss, although this occurs much later during life, usually as older adults.130,140
Individuals with Alport syndrome may also develop abnormalities in several parts of the eyes including the lens, retina and cornea. Eye abnormalities in XLAS and ARAS are very similar in presentation. Eye abnormalities are uncommon in ADAS. Anterior lenticonus is a condition in which the lenses of the eyes are shaped abnormally, specifically the lens bulges forward into the space (anterior chamber) behind the cornea. Anterior lenticonus can result in the need for glasses and sometimes leads to cataract formation. Anterior
8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com lenticonus occurs in about 20% of males with XLAS and often becomes apparent by late adolescence or early adulthood.
The retina, which is the nerve-rich, light-sensitive membrane that lines the back of the eyes, may also be affected, usually by pigmentary changes caused by the development of yellow or white flecks superficially located on the retina. These changes do not appear to affect vision. The cornea, which is the clear (transparent) outer layer of the eyes, may also be affected, although the specific abnormalities can vary. The effects on the cornea may be slowly progressive. Recurrent corneal erosions in which the outermost layer of the cornea (epithelium) does not stick (adhere) to the eye properly may occur. Recurrent corneal erosions can cause discomfort or severe eye pain, an abnormal sensitivity to light (photophobia), blurred vision, and the sensation of a foreign body (such as dirt or an eyelash) in the eye. Posterior polymorphous corneal dystrophy may also occur. Effects on the cornea may be slowly progressive. Both eyes may be affected; one eye can be more severely affected than the other. In severe cases, posterior polymorphous corneal dystrophy can cause swelling (edema) of a specific layer of the cornea, photophobia, the sensation of a foreign body (such as dirt or an eyelash) in the eye, and decreased vision.141,143
Additional symptoms can occur in certain individuals with Alport syndrome. In a small number of males, aneurysms of the chest or abdominal portions of the aorta, the main artery that carries blood away from the heart, have occurred. Aneurysms occur when the walls of blood vessels balloon or bulge outward, potentially rupturing causing bleeding within the body.144
9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Causes
Alport syndrome is caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The COL4A5 gene is located on the X chromosome. The COL4A3 and the COL4A4 genes are located on chromosome 2. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.139 X-linked Alport syndrome is caused by mutations in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females.
Females have two X chromosomes in their cells, but one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization,” and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.140,145
10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.146
Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be heterozygous because they inherit a normal copy of the gene from their mothers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female who is heterozygous for an X- linked disorder has a 50% chance with each pregnancy of having a heterozygous daughter, a 50% chance of having a daughter with two normal copies of the gene, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son. Approximately 15% of males with XLAS have a mutation that occurs randomly (spontaneously) for no known reason. In these cases, the mutation was not inherited from the mother.134
Autosomal recessive Alport syndrome is caused by mutations in both copies of either the COL4A3 or the COL4A4 genes. Autosomes are the non-sex chromosomes that carry most of genes. There are 22 autosomes and cells have two copies of each autosome, one inherited from the mother and the other inherited from the father. Each cell has two copies (alleles) of every autosomal gene. Autosomal recessive genetic disorders occur when an individual inherits an abnormal copy of a gene from each parent. If an
11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com individual receives one normal gene and one gene for the disease, the person will be heterozygous for the disease, and may or may not show symptoms. The risk for two heterozygous parents to both pass the defective gene and, therefore, have an affected child, is 25% with each pregnancy. The risk to have a child who is heterozygous like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.147,148
Autosomal dominant Alport syndrome is caused by mutations in one copy of either the COL4A3 gene or the COL4A4 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.149
Researchers have determined that the progression and severity of Alport syndrome tend to vary based upon the specific mutation present in a gene as well as the specific location of the mutation on the gene. This is known as genotype-phenotype correlation and allows clinicians to predict individuals who are at risk of early-onset kidney failure or more likely to develop extra- renal abnormalities. More than 1000 different mutations have been identified in XLAS.150
Some individuals with Alport syndrome have loss of genetic material (microdeletion) and loss of function of several adjacent genes (contiguous gene syndrome) on the long arm of the X chromosome, which affects both
12 nursece4less.com nursece4less.com nursece4less.com nursece4less.com the COL4A5 and COL4A6 genes. In addition to the classic symptoms of Alport syndrome, affected individuals can develop leiomyomatosis (tumors of smooth muscle that are not malignant). This is known as Alport syndrome with diffuse leiomyomatosis. Another disorder involving a contiguous gene syndrome associated with X-linked Alport syndrome is the AMME complex. The COL4A3, COL4A4, and COL4A5 genes create (encode) proteins known as alpha chains of collagen IV, a protein family that serves as the major structural component of basement membranes, specifically those of the kidneys, ears and eyes.
Basement membranes are delicate protein matrices that separate the thin outer layer of tissue (epithelium) of a structure from the underlying tissue. The basement membrane anchors the epithelium to the loose connective tissue beneath it and also serves as a barrier. The COL4A3 gene encodes the collagen IV alpha-3 chain. The COL4A4 gene encodes the collagen IV alpha- 4 chain. The COL4A5 gene encodes the collagen IV alpha-5 chain. Mutations in these genes result in low levels of functional copies of the corresponding proteins, which, in turn, lead to the improper health and maintenance of collagen IV.
The negative effects of collagen IV abnormalities result in the progressive damage to the basement membranes and ultimately the signs and symptoms of Alport syndrome.137,142,151 For example, in the kidneys the glomerular basement membrane (GBM) is a vital component of the walls of the small blood vessels (capillaries) that make up glomeruli. The glomeruli are the filtering units of the kidney. Blood flows through very small capillaries in each glomerulus where it is filtered through the GBM to form urine. Collagen IV acts to strengthen and hold the GBM together.
13 nursece4less.com nursece4less.com nursece4less.com nursece4less.com In individuals with Alport syndrome the GBM is initially thin and can develop microscopic ruptures that allow blood cells to leak into the urine, causing hematuria. The cells of the glomeruli respond to the abnormal collagen IV by laying down other proteins that lead to thickening of the GBM while impairing the GBM’s ability to keep protein out of the urine. This results in proteinuria. Further damage such as the formation of scar tissue (fibrosis) in the kidneys may also occur. Damage to the GBM and the kidneys is progressive, causing worsening kidney function and, in many cases, eventually kidney failure.139
Diagnosis
A diagnosis of Alport syndrome is suspected based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. The likelihood of diagnosis increases in individuals with a family history of Alport syndrome, kidney failure without known cause, early hearing loss or hematuria. A variety of specialized tests can help to confirm a suspected diagnosis.
Clinical Testing and Workup
The diagnostic approach to confirming a suspected diagnosis of Alport syndrome has been evolving over the past decade. While tissue studies (kidney or skin biopsy) are very useful tools in the evaluation of patients with hematuria, early genetic testing is becoming increasingly important. When clinical information and family history strongly suggest a diagnosis of Alport syndrome, genetic testing, using the techniques of next generation or whole exome sequencing, can confirm the diagnosis, establish the inheritance pattern and provide useful prognostic information. Genetic testing for Alport syndrome is offered by several commercial laboratories as
14 nursece4less.com nursece4less.com nursece4less.com nursece4less.com well as some hospital laboratories, but there is wide variation in insurance coverage.133,146
When genetic testing is unavailable or inaccessible, studies of tissue specimens (biopsies) are performed. A suspected diagnosis of XLAS may be confirmed by skin biopsy. A specific test known as immunostaining is performed on the sample. With immunostaining, an antibody that reacts against collagen type IV alpha-5 chain proteins is added to the skin sample. This allows physicians to determine whether a specific protein is present and in what quantity. Normally, alpha-5 chains are found in skin samples, but in males with XLAS they are nearly completely absent. Alpha-3 and alpha-4 chains are not present in the skin and, therefore, skin biopsies cannot be used to diagnose ARAS or ADAS.
A kidney biopsy may be also performed. A kidney biopsy can reveal characteristic changes to kidney tissue including abnormalities of the glomerular basement membrane (GBM) that can be detected by an electron microscope. Immunostaining can also be performed on a kidney biopsy sample. In addition to detecting alpha-5 chains, kidney samples can be assessed to determine whether type IV collagen alpha-3 or alpha-4 chains are present and in what quantity.148,152
Examination of urine samples (urinalysis) can reveal microscopic or gross amounts of blood (hematuria) in the urine. Hematuria may come and go (intermittent) in some cases, especially females with XLAS or individuals with ADAS. If kidney disease has progressed, elevated levels of protein can also be detected in urine samples.
15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Individuals diagnosed with Alport syndrome should undergo hearing tests that determine a person’s audible range for tones and speech (audiometry) and a complete eye (ophthalmological) exam. In cases where a parent has a known genetic abnormality (i.e., heterozygous mothers) prenatal diagnosis or pre-implantation genetic diagnosis (PGD) may be options. Prenatal diagnosis is possible through chorionic villi sampling (CVS) or amniocentesis. During CVS, fetal tissue samples are removed and enzyme tests (assays) are performed on cultured tissue cells (fibroblasts) and/or white blood cells (leukocytes). During amniocentesis, a sample of the fluid that surrounds the developing fetus is removed and studied.147
Pre-implantation genetic diagnosis can be performed on embryos created through in vitro fertilization. PGD refers to testing an embryo to determine whether it has the same genetic abnormality as the parent. Families interested such an option should seek the counsel of a certified genetics professional.
Treatment
The treatment of Alport syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, nephrologists, audiologists, ophthalmologists, and other health clinicians may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling is beneficial for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Due to the rarity of Alport syndrome, treatment trials that have been tested on a large group of patients are lacking. Various treatments have been reported in the medical literature as part of single case reports or small
16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with this disorder. Clinical guideline recommendations have been published that discuss the treatment of Alport syndrome, including information on identifying and treating children with a high risk of developing early-onset renal failure.135
Medications known as angiotensin-converting enzyme (ACE) inhibitors have been used to treat individuals with Alport syndrome. This off-label use may not be appropriate for all affected individuals and several factors must be considered before starting the therapy such as baseline kidney function, family history, and specific symptoms present. ACE inhibitors may be given when elevated levels of protein are detectable in the urine (overt proteinuria) in certain cases. These drugs are blood pressure medications that prevent (inhibit) an enzyme in the body from producing angiotensin II. Angiotensin II is a chemical that acts to narrow blood vessels and can raise blood pressure. ACE inhibitors in individuals with Alport syndrome have been shown to reduce proteinuria and slow the progression of kidney disease, delaying the onset of renal failure.153
Some individuals do not respond to or cannot tolerate ACE inhibitors. These individuals may be treated with drugs known as angiotensin receptor blockers (ARBs). ARBs prevent angiotensin II from binding to the corresponding receptors on blood vessels. In the medical literature, ACE inhibitor therapy or ARB therapy is recommended in certain individuals with Alport syndrome who show overt proteinuria. These therapies may also be considered in affected individuals who have small amounts of albumin in the urine (microalbuminuria), but have not yet developed overt proteinuria.
17 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Albumin is a marker for kidney disease because the kidney may leak small amounts of albumin when damaged.154
Although treatment may slow the progression of kidney disease in Alport syndrome, there is no cure for the disorder and no treatment that can completely stop kidney decline. The rate of progression of kidney decline in individuals with Alport syndrome is highly variable. In most affected individuals, kidney function eventually deteriorates to the point where dialysis or a kidney transplant is required. Dialysis is a procedure in which a machine is used to perform some of the functions of the kidney — filtering waste products from the bloodstream, helping to control blood pressure, and helping to maintain proper levels of essential chemicals such as potassium. End-stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant.140,155
A kidney transplant is preferred for individuals with Alport syndrome over dialysis and has generally been associated with excellent outcomes in treating affected individuals. Some individuals with Alport syndrome will require a kidney transplant in adolescence or the teen-age years, while others may not require a transplant until they are in their 40s or 50s. Most females with XLAS and some individuals will ADAS syndrome never require a transplant. If a kidney transplant is indicated, great care must be taken in selecting living related kidney donors to ensure that affected individuals are not chosen. Alport syndrome does not recur in kidney transplants. However, about 3% of transplanted Alport patients make antibodies to the normal collagen IV proteins in the transplanted kidney, causing severe inflammation of the transplant (anti-GBM nephritis).156
18 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Specific symptoms associated with Alport syndrome are treated by routine, accepted guidelines. For example, hearing aids may be used to treat hearing loss when appropriate. Hearing aids are usually effective in people with Alport syndrome because they do not lose the ability to distinguish one sound from another, as long as the sounds are amplified. Surgery to remove cataracts is performed when necessary.
Amyloidosis
Amyloidosis is a systemic disorder that is classified into several types. The different types of systemic amyloidosis are classified as primary, secondary or familial (hereditary). Primary amyloidosis (also called AL, or ‘light chain’) is the most common type of systemic amyloidosis. Primary amyloidosis results from an abnormality (dyscrasia) of plasma cells (a type of white blood cell) in the bone marrow and is closely related to multiple myeloma. Secondary amyloidosis (AA) is derived from the inflammatory protein serum amyloid A. Secondary amyloidosis occurs in association with chronic inflammatory disease such as the rheumatic diseases, Familial Mediterranean Fever, chronic inflammatory bowel disease, tuberculosis or empyema. Familial amyloidosis is a rare type of amyloidosis that is caused by an abnormal gene.
There are several abnormal genes that can cause hereditary amyloidosis, but the most common type of hereditary amyloidosis is called ATTR and caused by mutations in the transthyretin (TTR) gene. Senile amyloidosis, in which the amyloid is derived from wild-type (normal) transthyretin, is a slowly progressive disease that affects the hearts of elderly men. Amyloid deposits may occasionally occur in isolation without evidence of a systemic disease; isolated bladder or tracheal amyloid are the most common such presentations. Dialysis-related beta2-microglobulin amyloidosis is a type of
19 nursece4less.com nursece4less.com nursece4less.com nursece4less.com systemic amyloidosis that can occur in individuals who have experienced long-term kidney dialysis to remove accumulated impurities or wastes in the blood by mechanical filtration. This form of amyloidosis, also known as ABM2 (amyloid associated with the beta-2m protein), is associated with the aggregation of beta2-microglobulin, a type of amyloid protein that is cleared in the normally-functioning kidney. Dialysis-related beta2-microglobulin amyloidosis also occurs in patients with near end-stage renal disease. It does not affect individuals with normal or mildly reduced renal function or patients with a functioning renal transplant.157-159
In systemic amyloidosis, circulating amyloidogenic proteins form deposits in a variety of organs. Major systemic types include:
• AL (primary amyloidosis): Caused by acquired overexpression of clonal immunoglobulin light chains
• AF (familial amyloidosis): Caused by inheritance of a mutant gene encoding a protein prone to misfolding, most commonly transthyretin (TTR)
• ATTRwt (wild-type ATTR, previously termed senile systemic amyloidosis or SSA): Caused by misfolding and aggregation of wild-type TTR (wild- type ATTR)
• AA (secondary amyloidosis): Caused by aggregation of an acute phase reactant, serum amyloid A
Amyloidosis caused by aggregation of beta-2-microglobulin can occur in patients on long-term hemodialysis, but the incidence has declined with use of modern high-flow dialysis membranes.160
Localized forms of amyloidosis appear to be caused by local production and deposition of an amyloidogenic protein (most often immunoglobulin light
20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com chains) within the affected organ rather than by deposition of circulating proteins. Frequently involved sites include the central nervous system (CNS) (i.e., in Alzheimer disease), skin, upper or lower airways, lung parenchyma, bladder, eyes, and breasts.161
Primary Amyloidosis
Primary amyloidosis is caused by overproduction of an amyloidogenic immunoglobulin light chain in patients with a monoclonal plasma cell or other B cell lymphoproliferative disorder. Light chains can also form nonfibrillar tissue deposits (i.e., light chain deposition disease). Rarely, immunoglobulin heavy chains form amyloid fibrils (called AH amyloidosis). Common sites for amyloid deposition include the skin, nerves, heart, gastrointestinal (GI) tract (including the tongue), kidneys, liver, spleen, and blood vessels. Usually, a low-grade plasmacytosis is present in the bone marrow, which is similar to that in multiple myeloma, although most patients do not have true multiple myeloma (with lytic bone lesions, hypercalcemia, renal tubular casts, and anemia). However, about 10% to 20% of patients with multiple myeloma develop AL amyloidosis.162
Familial Amyloidosis
Familial amyloidosis is caused by inheritance of a gene encoding a mutated aggregation-prone serum protein, usually a protein abundantly produced by the liver. Serum proteins that can cause AF include transthyretin (TTR), apolipoprotein A-I and A-II, lysozyme, fibrinogen, gelsolin, and cystatin C. A recently identified form that is speculated to be familial is caused by the serum protein leukocyte chemotactic factor 2 (LECT2); however, a specific inherited gene mutation for this latter type has not been clearly demonstrated.
21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Amyloidosis caused by TTR (ATTR) is the most common type of AF. More than 100 mutations of the TTR gene have been associated with amyloidosis. The most prevalent mutation, V30M, is common in Portugal, Sweden, Brazil, and Japan, and a V122I mutation is present in about 4% of American blacks. Disease penetrance and age of onset are highly variable but are consistent within families and ethnic groups. ATTR causes peripheral sensory and autonomic neuropathy and cardiomyopathy. Carpal tunnel syndrome commonly precedes other neurologic disease manifestations. Vitreous deposits may develop due to production of mutant TTR by the retinal epithelium, or leptomeningeal deposits may develop if the choroid plexus produces mutant TTR.163,164
ATTRwt Amyloidosis
ATTRwt is caused by aggregation and deposition of wild-type TTR, clinically targeting the heart. ATTRwt is increasingly recognized as a cause of infiltrative cardiomyopathy in older men. The genetic and epigenetic factors leading to ATTRwt are unknown. Because ATTRwt and AL amyloidosis both can cause cardiomyopathy, and because amyloidogenic monoclonal gammopathies may be present in patients in this age group, it is essential to accurately type the amyloid so that patients with ATTRwt are not inappropriately treated with chemotherapy (which is used for AL).165
Secondary Amyloidosis
Secondary amyloidosis can occur secondary to several infectious, inflammatory, and malignant conditions and is caused by aggregation of isoforms of the acute-phase reactant serum amyloid A. Common causative infections include tuberculosis (TB), bronchiectasis, osteomyelitis, and leprosy. Predisposing inflammatory conditions include rheumatoid arthritis (RA), juvenile idiopathic arthritis, Crohn’s disease, inherited periodic
22 nursece4less.com nursece4less.com nursece4less.com nursece4less.com fever syndromes such as familial Mediterranean fever, and Castleman disease. Inflammatory cytokines (i.e., IL-1, tumor necrosis factor, IL-6) that are produced in these disorders or ectopically by tumor cells cause increased hepatic synthesis of serum amyloid A. Secondary amyloidosis shows a predilection for the spleen, liver, kidneys, adrenal glands, and lymph nodes. Involvement of the heart and peripheral or autonomic nerves occurs late in the disease course.166,167
Localized Amyloidosis
Localized amyloidosis outside the brain is most frequently caused by deposits of clonal immunoglobulin light chains and within the brain by amyloid beta protein. Localized amyloid deposits typically involve the airways and lung tissue, bladder and ureters, skin, breasts, and eyes. Rarely, other locally produced proteins cause amyloidosis, such as keratin isoforms that can form deposits locally in the skin.
Amyloid beta protein deposits in the brain contribute to Alzheimer disease or cerebrovascular amyloid angiopathy. Other proteins produced in the CNS can misfold, aggregate, and damage neurons, leading to neurodegenerative diseases (i.e., Parkinson disease, Huntington disease). Clonal immunoglobulin light chains produced by mucosal-associated lymphoid tissue in the GI tract, airways, and bladder can lead to localized AL in those organs.168
Amyloidosis is usually a multisystem disease resulting in a wide spectrum of clinical presentations. Consequently, a patient may present to, or be referred to, one of several subspecialists, most commonly a nephrologist, cardiologist or neurologist. Recent advances in therapy have rendered early and precise diagnosis critical if the patient is to fully benefit. Most patients have more
23 nursece4less.com nursece4less.com nursece4less.com nursece4less.com than one organ involved and therefore the finding of a combination of any of the features below should heighten the suspicion of amyloidosis.161
The kidney is the organ most commonly involved in AL, AA, and some rare hereditary forms but it is rarely involved in the familial forms caused by transthyretin mutations. Excessive amounts of protein in the urine (proteinuria) is the usual manifestation of renal involvement and is commonly heavy, resulting in the nephrotic syndrome. Less commonly, amyloid causes an excess of urea and other nitrogenous wastes in the blood (progressive azotemia) as the initial manifestation of renal disease. An abnormal accumulation of fluid (edema), such as swelling of the legs and abdomen, in the absence of heart failure is a feature of nephrotic syndrome, as is the presence of excess cholesterol in the blood (hypercholesterolemia) that may be profound. The kidneys often become small, pale and hard, but in amyloidosis, large kidneys are commonly seen as well. Renal tubular defects, renal vein blood clots (thrombosis) and high blood pressure (hypertension) may also be present. Amyloid may accumulate in other parts of the urogenital system, such as the bladder or urinary tubes (ureter).169,170
Amyloidosis frequently involves the heart. Amyloid infiltration of the heart results in ventricular wall thickening and the development of heart failure. Rapidly progressive congestive heart failure with thick ventricular walls is the classical presentation of AL cardiac amyloidosis. The heart is invariably involved in senile amyloidosis, often in TTR amyloidosis and almost never in the secondary amyloidosis. Common symptoms of heart involvement include an enlarged heart (cardiomegaly), an irregular heartbeat (arrhythmias), heart murmurs, and abnormalities of the heart seen on electrocardiograms (for example low voltage). Congestive heart failure is the most common cardiac complication of amyloidosis. Nodular deposits of amyloid may be
24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com present on the membranous sac that surrounds the heart (pericardium) and on the lining of the heart chambers or heart valves (endocardium).
Although less common than renal or cardiac involvement, neuropathy may be a significant problem in amyloidosis. Occasionally, it is the presenting and predominant feature of AL amyloidosis. In specific mutations of familial amyloidosis (particularly Met 30, originally known as familial amyloid polyneuropathy), it is the primary feature of the disease. The neuropathy is often painless and sensorimotor in nature although neuropathic pain may be occasionally significant. These symptoms may include sensory neuropathy with numbness and tingling sensations in the feet that progresses to the legs and eventually the upper extremities; motor neuropathy with loss of motion beginning in the feet and extending upward.
Carpal tunnel syndrome is commonly seen, not due to direct nerve involvement, but rather to soft tissue infiltration causing median nerve compression. In familial amyloidosis, the peripheral neuropathy is frequently accompanied by an autonomic neuropathy characterized by diarrhea and a decrease in the amount of sweat production (hypohidrosis), a sudden drop in blood pressure when the patient stands up (postural hypotension) and, in the male, erectile dysfunction. Postural hypotension may be profound and result in recurrent fainting (syncopal) episodes. Systemic amyloidosis does not involve the central nervous system, and is unrelated to Alzheimer’s disease.165,171,172
Amyloidosis may affect the liver and the spleen. Amyloid involvement in the spleen increases the risk of traumatic rupture of that organ. Some degree of hepatic involvement is common in AL amyloidosis. It is also common in AA amyloidosis but is not seen in TTR familial amyloidosis. In most cases,
25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com hepatic involvement is asymptomatic. An enlarged liver (hepatomegaly) and an enlarged spleen (splenomegaly) are the most notable signs. Generally, the amyloid-infiltrated liver feels very hard, and elevated liver enzymes (particularly alkaline phosphatase) and other liver function abnormalities may be detected early. Generally, the function of the liver is not significantly affected until late in the course of the disease. Elevation of bilirubin is an ominous sign and may portend hepatic failure. Hepatic amyloidosis rarely occurs in isolation and is usually associated with organ involvement elsewhere.162,164
Amyloidosis may also affect the gastrointestinal (digestive) system. Amyloid accumulation in the gastrointestinal tract may cause a lack of motility in the esophagus and the small and large intestines. Malabsorption, ulceration, bleeding, weak gastric activity, pseudo-obstruction of the GI tract, protein loss, and diarrhea may also occur. Loss of taste, and a difficulty eating solid foods because of enlargement of the tongue (macroglossia) from amyloid infiltration, may contribute to weight loss, or weight loss may be a non- specific manifestation of the systemic disease. In patients with autonomic neuropathy, gastric emptying is impaired, resulting in a sensation of early satiety.173,174
The skin is frequently involved in primary amyloidosis. Dermatologic involvement is almost exclusively limited to AL amyloid and consists of soft tissue, skin and vascular abnormalities. Periorbital purpura is a result of capillary fragility and may appear after coughing, sneezing, or straining for a bowel movement. Not infrequently, purpuric lesions may arise after such simple actions as rubbing the eyelids. Soft tissue infiltration may cause macroglossia and hoarseness, although examination of the vocal cords may appear normal. Lesions of the skin may be visible or may be so small that
26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com they may be seen only with a microscope. Waxy-looking papular lesions may appear on the face and the neck. They may also occur under the arms (axillary region), near the anus and the groin. Other areas that may be affected are the mucous areas such as the ear canal or tongue. Areas of swelling, hemorrhages under the skin (purpura), hair loss (alopecia), inflammation of the tongue (glossitis) and a dry mouth (xerostomia) may also be present.169,171
Problems with the respiratory system that are associated with amyloidosis often parallel cardiac symptoms. In the localized form of amyloidosis, air passages and ducts may be obstructed by amyloid deposits in the nasal sinuses, voice box (larynx) and throat (trachea) and bronchial tree. Fluid collecting in the pleural space (pleural effusion) is quite common in patients with congestive heart failure due to amyloidosis, but large recurrent pleural effusions disproportionate to the degree of heart failure suggest pleural amyloidosis.
Joint abnormalities (arthropathy) occur in amyloidosis due to the accumulation of amyloid deposits in the lining of joints (synovial membranes). This occurs in AL amyloidosis and occasionally in dialysis- related amyloidosis. Articular cartilage or the synovial membrane and fluid may become involved as well. Symptoms are similar to those of rheumatoid arthritis. Amyloid deposits in muscle tissue may cause muscle weakness and muscle changes (pseudomyopathy). Symptoms of amyloidosis may also be manifested by bleeding disorders. These may result from deficiency of certain clotting factors or small amyloid deposits in blood vessels within the skin.175
27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Dialysis-related beta2-microglobulin amyloidosis usually affects the bones and joints. Initial symptoms include carpal tunnel syndrome, shoulder pain and inflammation of the tendon sheaths of the hands. Case reports of severe pulmonary hypertension and heart failure also exist.
Suspicion of amyloidosis should be increased in patients with a progressive multisystem disease process. Renal amyloid deposits typically occur in the glomerular membrane leading to proteinuria, but in about 15% of cases the tubules are affected, causing azotemia with minimal proteinuria. These processes can progress to nephrotic syndrome with marked hypoalbuminemia, edema, and anasarca or to end-stage renal disease. Hepatic involvement causes painless hepatomegaly, which may be massive. Liver function tests typically suggest intrahepatic cholestasis with elevation of alkaline phosphatase and later bilirubin, although jaundice is rare. Occasionally, portal hypertension develops, with resulting esophageal varices and ascites.
Airway involvement leads to dyspnea, wheezing, hemoptysis, or airway obstruction. Infiltration of the myocardium causes a restrictive cardiomyopathy, eventually leading to diastolic dysfunction and heart failure; heart block or arrhythmia may occur. Hypotension is common. Peripheral neuropathy with paresthesias of the toes and fingers is a common presenting manifestation in AL and ATTR amyloidoses. Autonomic neuropathy may cause orthostatic hypotension, erectile dysfunction, sweating abnormalities, and GI motility disturbances. Cerebrovascular amyloid angiopathy most often causes spontaneous lobar cerebral hemorrhage but some patients have brief, transient neurologic symptoms. GI amyloid may cause motility abnormalities of the esophagus and small and large intestines. Gastric atony, malabsorption, bleeding, or pseudo-
28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com obstruction may also occur. Macroglossia is common in AL amyloidosis. Amyloidosis of the thyroid gland may cause a firm, symmetric, nontender goiter resembling that found in Hashimoto thyroiditis. Other endocrinopathies can also occur. Lung involvement (mostly in AL amyloidosis) can be characterized by focal pulmonary nodules, tracheobronchial lesions, or diffuse alveolar deposits. Amyloid vitreous opacities and bilateral scalloped pupillary margins develop in several hereditary amyloidoses.166,177
Other manifestations include bruising, including bruising around the eyes (raccoon eyes), which is caused by amyloid deposits in blood vessels. Amyloid deposits cause weakening of the blood vessels, which may rupture after minor trauma, such as sneezing or coughing.
Amyloidosis is caused by abnormal folding of proteins leading to fibril formation in one or more body organs, systems or soft tissues. These clumps of protein are called amyloid deposits and the accumulation of amyloid deposits causes the progressive malfunction and eventual failure of the affected organ. Normally, proteins are broken down at about the same rate as they are produced, but these unusually stable amyloid deposits are deposited more rapidly than they can be broken down.
The cause of primary amyloidosis (AL) is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody). Usually an excess amount of antibody protein is produced and the abnormal light chain portion or the whole antibody molecule accumulates in the body tissues in the form of amyloid deposits. Secondary amyloidosis is caused by the inflammatory disease process that is part of the underlying disease. Approximately 50% of
29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.171,178
Familial amyloidosis is caused by an abnormality in the gene for one of several particular proteins. The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the gene for transthyretin. More than 100 different mutations in the transthyretin gene have been reported and the most common mutation has been termed V30M. Different TTR mutations are associated with amyloidosis that affects different organ systems. Rarely, mutations in genes for proteins that cause amyloidosis are fibrinogen A alpha chain, apolipoprotein A1 and A2, gelsolin, and cystatin C.
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. All the hereditary amyloidoses follow autosomal dominant inheritance, which means that the presence of one copy of a mutated gene can cause the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females; however, not every person getting the gene will get sick with amyloidosis.162,179
The exact cause of dialysis-related beta2-microglobulin amyloidosis is not fully understood. A normally-functioning kidney can clear out the amyloid protein, beta 2-microglobulin. In some individuals on long-term dialysis or some individuals on continuous ambulatory peritoneal dialysis (CAPD), the kidneys’ inability to function properly leads to the abnormal retention and accumulation of the beta2-microglobulin protein. Some individuals with near end-stage renal failure have also developed this form of amyloidosis.
30 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Although this retention and accumulation is believed to be the main underlying factor, additional factors are required for the disorder to develop, which is why only a percentage of individuals on dialysis develop dialysis- related beta2-microglobuin amyloidosis.167,180
It is estimated that there are approximately 4000 new cases of AL amyloidosis annually in the U.S., though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. Primary amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.
Individuals at risk for amyloidosis include those with chronic inflammatory diseases such as rheumatic arthritis, psoriatic arthritis, chronic juvenile arthritis, ankylosing spondylitis in children, inflammatory bowel disease, and familial Mediterranean fever. People with chronic infectious diseases such as tuberculosis, leprosy, bronchiectasis, chronic osteomyelitis, and chronic pyelonephritis are also at risk. Secondary amyloidosis occurs in less than 5% of individuals with these conditions.
Familial amyloidosis caused by a transthyretin mutation occurs in approximately 1 in 100,000 Caucasians in the U.S, and more commonly in African Americans (approximately 4% in that population). This condition is prevalent in Portugal, Sweden, Japan, Ireland, Spain, France, Finland, Germany and Greece. Symptoms usually begin between 40 and 65 years of age.162,167
Though both familial and secondary amyloidosis are probably less common than immunoglobulin light chain (AL) amyloidosis, senile amyloidosis is
31 nursece4less.com nursece4less.com nursece4less.com nursece4less.com probably more common, but considerably underdiagnosed. Particularly in the case of AL amyloidosis, early diagnosis is the key to survival and post treatment quality of life. The diagnosis of amyloidosis is suspected following a detailed patient history and clinical evaluation but requires a biopsy of muscle, bone or fatty tissue to confirm the presence of amyloid. If the disease is suspected on clinical grounds, a biopsy of the involved organ will give the highest yield. The biopsy material is examined microscopically and is stained with a dye called Congo red that will produce a green color when looked at in a polarizing microscope if amyloid is present. When amyloidosis is diagnosed on a tissue biopsy it is essential that the affected individual be further evaluated to determine what organs are affected.
Once a tissue biopsy of amyloid has been established, it is mandatory to determine the type of amyloidosis. In AL amyloidosis, manifestations of a plasma cell dyscrasia will be found 98% of the time. In 2% of cases, a B-cell lymphoma is identified as the cause of AL amyloidosis. The specific tests that are used to make a diagnosis of the AL amyloidosis type are both immunofixation and protein electrophoresis of the blood and urine, bone marrow biopsy with immunochemical staining of plasma cells for kappa and lambda light chains and a serum free light chain assay. The dermatologic manifestations of AL amyloid may strongly suggest the diagnosis, particularly when other organ involvement suggests a systemic disease. A diagnosis of AL amyloidosis is confirmed by the presence of periorbital purpura, which is a result of capillary fragility or macroglossia.171,177,180
The diagnosis of transthyretin (TTR) hereditary amyloidosis can be confirmed by performing molecular genetic testing for mutations in the TTR gene on a blood sample. In the absence of mutations of transthyretin, very rare forms of familial amyloid may be present. If the patient is an elderly
32 nursece4less.com nursece4less.com nursece4less.com nursece4less.com man with clinically isolated cardiac involvement, the most likely diagnosis is senile systemic amyloid (senile cardiac amyloid), a condition in which wild- type (normal) transthyretin is deposited in the heart.173,181
Specific immunostaining (for example, immunogold electron microscopy) of appropriately preserved tissue is available at specialized centers and offers a high specificity for determining the type of amyloid. In difficult diagnostic cases, mass spectrometry is able to determine precisely the molecular structure of the amyloid deposits. This technique is being used more and more frequently. A technique called radiolabeled serum amyloid P (SAP) scanning is available in a few centers in Europe that specialize in amyloidosis. This test is used to monitor the accumulation of amyloid deposits.
In individuals on long-term dialysis or with end stage renal failure, lab tests may be performed that can analyze blood or urine samples to detect increased levels B2M protein. Patients are screened for organ involvement beginning with noninvasive testing:161,177
• Kidneys: Urinalysis and measurement of serum BUN and creatinine
• Liver: Liver function tests
• Heart: ECG and measurement of brain (B-type) natriuretic peptide (BNP) or N-terminal-pro-BNP (NT-proBNP) and troponin
• Lungs: Chest x-ray, chest CT, and/or pulmonary function tests
Cardiac involvement can be suggested by low voltage on electrocardiogram (ECG), caused by a thickened ventricle, and/or dysrhythmias. If cardiac involvement is suspected because of symptoms, ECG, or cardiac biomarkers, echocardiography is done to measure diastolic relaxation and systolic function and to screen for biventricular hypertrophy. In ambiguous cases,
33 nursece4less.com nursece4less.com nursece4less.com nursece4less.com cardiac MRI can be done to detect delayed subendocardial gadolinium enhancement, a characteristic finding. Technetium pyrophosphate nuclear imaging is a newly validated, highly sensitive and specific test for ATTR amyloid cardiomyopathy.167
Prognosis depends on the type of amyloidosis and the organ system involved, but with appropriate disease-specific and supportive care, many patients have an excellent life expectancy. AL complicated by severe cardiomyopathy still has the poorest prognosis, with median survival of < 1 year. Untreated ATTR amyloidosis usually progresses to end-stage cardiac or neurologic disease within 5 to 15 year. ATTRwt was once thought to have the slowest progression of any systemic amyloidosis involving the heart; however, patients with ATTRwt do progress to symptomatic heart failure and death within a few years of diagnosis.171 Prognosis in AA amyloidosis depends largely upon the effectiveness of treatment of the underlying infectious, inflammatory, or malignant disorder.
Treatment
Currently, there are specific treatments for most forms of amyloidosis, although some therapies are investigational. For all forms of systemic amyloidosis, supportive care measures can help relieve symptoms and improve quality of life.
The type of treatment available is driven by the type of amyloidosis and the clinical state of the patient. In AL amyloidosis, the cause is the abnormal white blood cell (usually a plasma cell) and as such, chemotherapy aimed at eradicating those cells forms the cornerstone of treatment. Various regimens have been studied but the ones with the most historical evidence are melphalan and dexamethasone given orally or high-dose melphalan given
34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com intravenously with autologous stem cell support. Both are equally effective but the treatments and side effects are different. High dose melphalan with stem cell support is an involved treatment that often involves a 2-3 week hospital stay and a few months of additional recovery time. The use of oral melphalan on a monthly basis is less toxic, but is associated with a higher risk of treatment-related leukemia.
Newer agents active in multiple myeloma (another disease of abnormal plasma cells), such as bortezomib or lenalidomide, are also very effective in AL and have been shown to provide a benefit in patients with relapsed disease. Often times, these drugs are incorporated into upfront treatment. Currently, most patients not getting high dose melphalan with stem cell support are having getting novel therapies upfront. The combination of bortezomib, cyclophosphamide and dexamethasone is associated with good tolerability and rapid responses. The specific treatment for any individual has to be personalized to their unique situation.169,182 The two most important determinants of long-term survival with AL are the presence and extent of cardiac involvement and hematologic response to therapy.
There are several exciting new agents intended to cause resorption of amyloid from affected organs. This might offer an ability to treat the sick organs directly. The most advanced of these studies is with NEOD001, which has shown some benefit for patients whose underlying plasma cell disease had already been treated, and is currently being studies in combination with bortezomib based therapy in the upfront setting.171
Supportive therapy (treatment of congestive heart failure, attention to nutrition, treatment of autonomic neuropathy, etc.) is a very important concomitant measure. Given the complexity of the disease, it is
35 nursece4less.com nursece4less.com nursece4less.com nursece4less.com recommended that treatment be performed in the center with experience of amyloidosis, or at least that the patient should have an initial evaluation at such a center, with continued communication during treatment in the local community.
Familial TTR amyloidosis is treated, if possible, by removal of the source of the abnormal TTR production. Since the dominant source is the liver, liver transplantation is currently the treatment of choice in carefully selected patients whose disease is not too far advanced. Tafamidis is a drug recently approved for familial amyloid polyneuropathy (FAP). This agent is being tested in ongoing trials for other forms of ATTR. Patisiran and revusiran are also being testing for ATTR, focused on reducing levels of TTR that form the amyloid. Genetic counseling is recommended for individuals with hereditary amyloidosis and their family members.162
In senile amyloidosis, therapy is supportive, but both for this disease and for ATTR, pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated. Clinical testing of the nonsteroidal agent diflunisal, a transthyretin stabilizer, is ongoing.
The mainstay of secondary amyloidosis treatment is therapy of the underlying disease. Renal transplantation has been performed successfully for renal disease due to secondary amyloidosis. Eprodisate is a small molecule that inhibits the formation of amyloid fibrils, and which seems to have a modest clinical effect in patients with secondary amyloidosis.
36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Supportive Care
Supportive care measures are directed at the affected organ system.160,170,171
Renal
Patients with nephrotic syndrome and edema should be treated with salt and fluid restriction, and loop diuretics; because of the ongoing protein loss, protein intake should not be restricted. Kidney transplantation is an option when the underlying disease process is controlled, and can provide long- term survival comparable to that in other renal diseases.
Cardiac
Patients with cardiomyopathy should be treated with salt and fluid restriction and loop diuretics. Other drugs for heart failure, including digoxin, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, and beta-blockers are poorly tolerated and contraindicated. Heart transplantation has been successful in carefully selected patients with AL amyloidosis and severe cardiac involvement. To prevent recurrence in the transplanted heart, patients must be given aggressive chemotherapy directed at clonal plasma cell disorder.
Gastrointestinal
Patients with diarrhea may benefit from loperamide. Those with early satiety and gastric retention may benefit from metoclopramide.
Nerves
In patients with peripheral neuropathy, gabapentin or pregabalin may relieve pain.
37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Orthostatic hypotension often improves with high doses of midodrine; this drug can cause urinary retention in older males, but supine hypertension is rarely a problem in this population. Support stockings can also help, and fludrocortisone can be used in patients without peripheral edema, anasarca, or heart failure.
Type-specific Treatment
In AL amyloidosis, prompt initiation of antiplasma cell therapy is essential to preserve organ function and prolong life. Most drugs used for multiple myeloma have been used in AL amyloidosis; choice of drug, dose, and schedule often must be modified when organ function is impaired. Chemotherapy using an alkylating agent (i.e., melphalan, cyclophosphamide) combined with corticosteroids was the first regimen to show any benefit. High-dose IV melphalan, combined with autologous stem cell transplantation can be highly effective in selected patients. Proteasome inhibitors (i.e., bortezomib) and immunomodulators (i.e., lenalidomide) also can be effective. Combination and sequential regimens are being investigated. Localized AL can be treated with low-dose external beam radiation therapy because plasma cells are highly radiosensitive.
ATTR amyloidosis, liver transplantation — which removes the site of synthesis of the mutant protein — can be effective in certain TTR mutations with early neuropathy and no heart involvement. Recently, certain drugs have been shown to stabilize TTR in the plasma, preventing misfolding and fibril formation and inhibiting neurologic disease progression while preserving quality of life. These TTR stabilizers include diflunisal, which is widely available, and tafamidis, which is available in Europe, Brazil, and Japan. TTR gene silencing using anti-sense RNA or RNA interference to block
38 nursece4less.com nursece4less.com nursece4less.com nursece4less.com translation of mRNA into protein effectively reduces serum levels of TTR and is in clinical trials.
ATTRwt amyloidosis, TTR stabilization should also be effective but has not been tested; liver transplantation is not effective for patients with ATTRwt because the amyloidogenic protein is wild-type TTR.
In AA amyloidosis caused by familial Mediterranean fever, colchicine 0.6 mg orally once/day or bid is effective. Colchicine is not effective in other disorders predisposing to AA amyloidosis. For other AA types, treatment is directed at the underlying infection, inflammatory disease, or cancer. Eprodisate, a sulfonated molecule that alters the stability of AA amyloid deposits, is a promising drug now under study.163,176,183
Goodpasture Syndrome
Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging). Autoimmune syndromes occur when the body's natural defenses (antibodies) against invading or "foreign" organisms begin to attack the body's own tissue, often for unknown reasons.
Symptoms of Goodpasture syndrome include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia). In many cases, Goodpasture syndrome may result in an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). In some cases of Goodpasture syndrome, affected individuals
39 nursece4less.com nursece4less.com nursece4less.com nursece4less.com have had an upper respiratory tract infection before the development of the disorder. The exact cause of Goodpasture syndrome is not known.184
Goodpasture syndrome is a pulmonary-renal syndrome, which is a group of acute illnesses involving the kidneys and lungs. Goodpasture syndrome includes all of the following conditions:185
• Glomerulonephritis — inflammation of the glomeruli, which are tiny clusters of looping blood vessels in the kidneys that help filter wastes and extra water from the blood
• The presence of anti-glomerular basement membrane (GBM) antibodies; the GBM is part of the glomeruli and is composed of collagen and other proteins
• Bleeding in the lungs
In Goodpasture syndrome, immune cells produce antibodies against a specific region of collagen. The antibodies attack the collagen in the lungs and kidneys. Ernest Goodpasture first described the syndrome during the influenza pandemic of 1919 when he reported on a patient who died from bleeding in the lungs and kidney failure. Diagnostic tools to confirm Goodpasture syndrome were not available at that time, so it is not known whether the patient had true Goodpasture syndrome or vasculitis. Vasculitis is an autoimmune condition — a disorder in which the body’s immune system attacks the body’s own cells and organs — that involves inflammation in the blood vessels and can cause similar lung and kidney problems. Goodpasture syndrome is sometimes called anti-GBM disease. However, anti-GBM disease is only one cause of pulmonary-renal syndromes, including Goodpasture syndrome. Goodpasture syndrome is fatal unless quickly diagnosed and treated.186
40 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Today, the term Goodpasture syndrome is often used to describe the combination of rapidly progressive glomerulonephritis (RPGN), pulmonary hemorrhage, and anti-GBM antibodies. However, some researchers use Goodpasture syndrome to refer to those patients with the characteristic clinical features from any cause and Goodpasture disease to describe those who in addition have anti-GBM antibodies. The term anti-GBM disease is also widely used to describe any patient with the typical autoantibodies, regardless of clinical features.186
The causes of Goodpasture syndrome are not fully understood. People who smoke or use hair dyes appear to be at increased risk for this condition. Exposure to hydrocarbon fumes, metallic dust, and certain drugs, such as cocaine, may also raise a person’s risk. Genetics may also play a part, as a small number of cases have been reported in more than one family member.
Clinical Features
Goodpasture syndrome exhibits a bimodal age distribution, with peak incidences in the third and sixth decades of life, and a slight preponderance toward males. Most patients present with RPGN and lung hemorrhage, although about one third present with isolated glomerulonephritis. Rarely, patients present with isolated lung hemorrhage without kidney failure, although many of these patients will experience hematuria and proteinuria. General malaise, fatigue, and weight loss are the most common systemic features and may relate to anemia.187
Pulmonary Hemorrhage
Pulmonary hemorrhage occurs in about two thirds of patients and is more common in young men. It may precede the development of kidney disease. Patients often complain of breathlessness and cough, which may be
41 nursece4less.com nursece4less.com nursece4less.com nursece4less.com accompanied by minor or massive hemoptysis. Cigarette smoking, inhaled toxins, sepsis, or fluid overload can trigger hemoptysis.
Clinical signs include tachypnea, respiratory crackles, and eventually cyanosis, but these are often indistinguishable from the signs of pulmonary edema or infection. Radiographic features are nonspecific but usually involve patchy or diffuse alveolar shadowing in the central lung fields. The most sensitive test is an elevation in the carbon monoxide diffusion capacity of the lungs, which is caused by the presence of hemoglobin in the alveolar spaces. Bronchoscopy may reveal diffuse hemorrhage, but it is perhaps of more importance in excluding infection. Despite the common presentation of pulmonary hemorrhage, long-term pulmonary sequelae are uncommon in treated patients.188
Hematuria
Although occasional patients may present with isolated hematuria or mildly reduced kidney function, they most commonly present with kidney failure as a result of RPGN. The clinical features are not distinguishable from those of any other cause of RPGN, although, unlike cases of RPGN that are associated with systemic vasculitis, systemic features (other than lung hemorrhage) are uncommon. Urine microscopy typically shows numerous erythrocytes of glomerular origin, red-cell casts, and mild to moderate proteinuria; nephrotic-range proteinuria is rare unless there is a secondary concurrent glomerular disease such as membranous nephropathy. Hypertension and oliguria are late features. Renal ultrasonography usually reveals normal- sized kidneys and is helpful in excluding other kidney disorders.189
42 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Causes
Goodpasture syndrome develops due to unknown causes. Environmental factors such as hydrocarbon chemical exposure, cigarette smoke, or infections such as influenza may play a role in the development of the disorder. It is not known why simple infections can progress to Goodpasture syndrome in some people. When infection occurs, the body’s natural defenses (antibodies) fight the invading organisms (i.e., viruses or bacteria). In autoimmune disorders, antibodies attack healthy tissue for no apparent reason. Pulmonary hemorrhage has been frequently associated with smoking in individuals with Goodpasture syndrome. In Goodpasture syndrome, certain antibodies (anti-glomerular basement membrane [anti-GBM] antibodies) may be produced and circulate throughout the blood. These antibodies may damage the delicate membranes that line the lungs and kidneys or the tiny blood capillaries within the lungs and kidneys.184,190
In some cases, individuals with Goodpasture syndrome may have an association with human leukocyte antigens (HLAs). HLAs are proteins that play an important role in the body’s immune system; they influence the outcome of transplantation and appear to affect an individual’s predisposition to certain diseases. However, the implications of such findings are not fully understood. Goodpasture syndrome has been reported in more than one family member (i.e., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances, such as due to particular environmental factors (multifactorial inheritance).191
43 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Symptoms
Symptoms of Goodpasture syndrome include:
• Shortness of breath
• Coughing up blood
• Fever
• Unplanned weight loss
• Fatigue (may be a symptom of anemia that results from blood loss)
Symptoms can quickly become severe. Occasionally symptoms are severe enough to cause the lungs to fail and people to have severe difficulty breathing, gasping, and cyanosis. When the lungs fail, the tissues of the body do not receive enough oxygen, and the person may die. Large amounts of blood can be lost. At the same time, the kidneys can rapidly fail. There may be small amounts of blood in the urine.192
The major symptoms of Goodpasture syndrome are excessive bleeding into the lungs (pulmonary hemorrhaging) and inflammation of the filtering structures (glomeruli) or the kidneys (glomerulonephritis). In some cases, an upper respiratory tract infection may precede the development of the disorder. General symptoms associated with Goodpasture syndrome may include fever, nausea, and fatigue.193
Pulmonary hemorrhaging may lead to episodes where affected individuals cough up blood (hemoptysis). The severity of this finding may range from a few flecks to excessive amounts of blood. Affected individuals may also exhibit difficult breathing, fatigue, chest pain, a dry rasping sound from the throat (rhonchus), and/or frequent coughing. In rare cases, affected individuals may exhibit abnormal accumulation of fluid (edema) in the tissue of the lungs. Pulmonary abnormalities are usually noted before or
44 nursece4less.com nursece4less.com nursece4less.com nursece4less.com simultaneous to kidney renal abnormalities in approximately 70 percent of the cases.
Inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) may lead to an inability of the kidneys to process waste products from the blood and excrete them in the urine (acute renal failure). Renal failure usually leads to a decrease in the amount of urine the body produces. Additional symptoms associated with renal failure may include pallor, drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach and/or a decrease in the amount of circulating red blood cells (anemia). In rare cases, affected individuals may exhibit high blood pressure and/or pain and swelling of the joints (arthritis). In some cases, symptoms of Goodpasture syndrome may recur after treatment.184,190
Treatment
Mild forms of Goodpasture syndrome may be treated with the use of drugs that suppress or hinder the effectiveness of the body's immune system (immunosuppressive drugs). Corticosteroids such as prednisone may be administered to control bleeding in the lungs (pulmonary hemorrhaging). Many affected individuals may be treated with plasmapheresis. This procedure is a method for removing unwanted substances (toxins, damaging antibodies, and metabolic substances) from the blood. Blood is removed from the patient and blood cells are separated from plasma. The patient's plasma is then replaced with other human plasma and the blood is transfused into the patient. This therapy is still under investigation to analyze side effects and effectiveness. Plasmapheresis is often administered in conjunction with corticosteroid treatment.193
45 nursece4less.com nursece4less.com nursece4less.com nursece4less.com In severe and repeated cases of Goodpasture syndrome affected individuals may be treated with a procedure where waste products are removed from the blood (dialysis). In the most severe cases, a kidney transplant may be needed.
Untreated anti-GBM disease is usually rapidly fatal, and, in the absence of treatment, kidney failure is expected. However, since its introduction in the 1970s, treatment with plasma exchange, cyclophosphamide, and corticosteroids (together with dialysis when required) now allows the great majority of patients to survive. The rationale behind this treatment regimen is that plasma exchange rapidly removes circulating anti-GBM antibodies, whereas cyclophosphamide prevents further antibody synthesis. There has been only one small trial of plasma exchange compared with drug treatment alone, and it suggested a trend toward improved outcome; however, the widely reported improvement in mortality and in kidney function after introduction of the treatment regimen described previously has led to its widespread use.
All patients should be considered for treatment; however, those with limited kidney disease who present dialysis dependent with extensive crescentic glomerulonephritis are least likely to respond, and many clinicians avoid treating them with immunosuppressive therapy. Some patients have been treated with intravenous methylprednisolone, but there is no convincing evidence that it confers a benefit, and it may be associated with a greater risk for infection. Similarly, pulsed intravenous cyclophosphamide has not been formally tested but has been shown to be equivalent to daily oral dosing in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis with moderate kidney involvement, and it has been used by some clinicians in small cohorts.
46 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Cyclosporine, mycophenolate mofetil, and the anti-CD20 monoclonal antibody rituximab have occasionally been used in patients unresponsive to other therapy, but their role is not yet clear, and they cannot be recommended as first-line therapy. In general, long-term treatment is not necessary, and patients can stop cyclophosphamide after 3 months. Some clinicians then change to azathioprine, but there is little evidence that this is necessary. Steroids may be tapered off after approximately 6 months.187,191
Most patients now survive the acute disease, although it is important to note that pulmonary hemorrhage and infection remain as causes of death. In recent series, 1-year patient survival was 75% to 90%, but only about 40% of survivors recovered independent kidney function. The serum creatinine concentration usually starts to decrease within 1 or 2 weeks after the initiation of treatment, and most patients with a creatinine level of less than 6.8 mg/dl at presentation recover kidney function. However, it has been reported that those who have a creatinine level greater than 6.8 mg/dl or who are oliguric rarely recover kidney function. A single-center study of 71 treated patients showed that almost all of the patients with a creatinine level of less than 5.7 mg/dl recovered kidney function as did most of those with a level greater than 5.7 mg/dl, but not those requiring dialysis. Crescent scores of greater than 50% are usually, but not always, associated with a poor kidney prognosis.
Patients presenting with dialysis-dependent kidney failure may therefore not benefit from immunosuppression unless they also have pulmonary hemorrhage. This is in marked contrast to the outcome in patients with ANCA-associated rapidly progressive glomerulonephritis (RPGN), in whom the majority should recover kidney function, even if presenting with a creatinine level of greater than 6.8 mg/dl or if dialysis is ongoing. One
47 nursece4less.com nursece4less.com nursece4less.com nursece4less.com potential reason for immunosuppression in dialysis-dependent patients is the more rapid elimination of anti-GBM antibodies, which may otherwise persist for years, to enable prompt transplant if a living kidney donor is available.190,191
Granulomatosis With Polyangiitis (Wegener’s Granulomatosis)
Granulomatosis with polyangiitis (GPA) is a condition that causes inflammation that primarily affects the respiratory tract (including the lungs and airways) and the kidneys. This disorder is also commonly known as Wegener granulomatosis. A characteristic feature of GPA is inflammation of blood vessels (vasculitis), particularly the small- and medium-sized blood vessels in the lungs, nose, sinuses, windpipe, and kidneys, although vessels in any organ can be involved. Polyangiitis refers to the inflammation of multiple types of vessels, such as small arteries and veins. Vasculitis causes scarring and tissue death in the vessels and impedes blood flow to tissues and organs.194
Another characteristic feature of GPA is the formation of granulomas, which are small areas of inflammation composed of immune cells that aid in the inflammatory reaction. The granulomas usually occur in the lungs or airways of people with this condition, although they can occur in the eyes or other organs. As granulomas grow, they can invade surrounding areas, causing tissue damage.
The signs and symptoms of GPA vary based on the tissues and organs affected by vasculitis. Many people with this condition experience a vague feeling of discomfort (malaise), fever, weight loss, or other general symptoms of the body's immune reaction. In most people with GPA,
48 nursece4less.com nursece4less.com nursece4less.com nursece4less.com inflammation begins in the vessels of the respiratory tract, leading to nasal congestion, frequent nosebleeds, shortness of breath, or coughing. Severe inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose).195,196
The kidneys are commonly affected in people with GPA. Tissue damage caused by vasculitis in the kidneys can lead to decreased kidney function, which may cause increased blood pressure or blood in the urine, and life- threatening kidney failure. Inflammation can also occur in other regions of the body, including the eyes, middle and inner ear structures, skin, joints, nerves, heart, and brain. Depending on which systems are involved, additional symptoms can include skin rashes, inner ear pain, swollen and painful joints, and numbness or tingling in the limbs.197,198 GPA is most common in middle-aged adults, although it can occur at any age. If untreated, the condition is usually fatal within 2 years of diagnosis. Even after treatment, vasculitis can return.
The genetic basis of GPA is not well understood. Having a particular version of the HLA-DPB1 gene is the strongest genetic risk factor for developing this condition, although several other genes, some of which have not been identified, may be involved. It is likely that a combination of genetic and environmental factors leads to GPA. Such disorders occur when the immune system malfunctions and attacks the body's own tissues and organs.
Approximately 90 percent of people with GPA have an abnormal immune protein called an anti-neutrophil cytoplasmic antibody (ANCA) in their blood. GPA is an autoimmune disorder; antibodies normally bind to specific foreign particles and germs, marking them for destruction, but ANCAs attack normal
49 nursece4less.com nursece4less.com nursece4less.com nursece4less.com human proteins. Most people with GPA have an ANCA that attacks the human protein proteinase 3 (PR3). A few affected individuals have an ANCA that attacks a protein called myeloperoxidase (MPO). When these antibodies attach to the protein they recognize, they trigger inflammation, which contributes to the signs and symptoms of GPA.199,200
The HLA-DPB1 gene belongs to a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders (such as viruses and bacteria). Each HLA gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins. A particular variant of the HLA-DPB1 gene called HLA- DPB10401 has been found more frequently in people with GPA, especially those with ANCAs, than in people without the condition. Because the HLA- DPB1 gene is involved in the immune system, changes in it might be related to the autoimmune response and inflammation in the respiratory tract and kidneys characteristic of GPA. However, it is unclear what specific role the HLA-DPB10401 gene variant plays in development of this condition.195
Granulomatosis with polyangiitis is a rare disorder that affects males and females in equal numbers. In most people, onset is after the fourth or fifth decade of life; however, the disorder can occur at any age. There are some studies that suggest that girls are affected more often than boys when the disorder occurs in childhood. There are also studies that suggest that males are more likely to have severe disease, while females are more likely to have localized disease. Estimates of the frequency of granulomatosis with polyangiitis vary greatly depending upon the specific population being studied. Because the disorder often goes unrecognized, researchers believe that it is under-diagnosed, making it difficult to determine the true frequency
50 nursece4less.com nursece4less.com nursece4less.com nursece4less.com in the general population. Granulomatosis with polyangiitis affects Caucasians most often, but can affect people of any race or ethnic background anywhere in the world.201,202
The incidence of GPA is estimated to be 8–10 cases per one million depending on geographic location. It has been suggested that the incidence of GPA is increasing, however this may simply reflect the availability of new diagnostic modalities and serologic tests such as ANCAs that allows a more frequent diagnosis. The age of symptoms onset has a wide distribution with a peak incidence at 64–75 years of age. Previous studies showed that GPA can occur in children with 8–15% of cases occurring in patients age 19 or younger. Although slight male predominance has been reported in few case series a recent study including 158 patients showed no sex predilection. GPA is most frequently reported in white Caucasian patients but can be seen in all racial and ethnic groups.203,204
Classic GPA, as detailed by Godman and Churg in 1954, includes the triad of necrotizing granuloma of upper and lower respiratory system, systemic vasculitis, and necrotizing glomerulonephritis. The kidneys are usually spared in the limited form of GPA. Classic GPA can sometimes begin with limited organ involvement and then convert to a more generalized form with nose, lung and kidney being affected. Patients with GPA usually present with nonspecific symptoms of generalized systemic illness including fever, malaise, weight loss, arthralgia, and myalgia.205 The earliest complaints, which are also the most common reasons for seeking medical attention, are usually related to upper respiratory tract problems including sinus pain, purulent nasal discharge, epistaxis, nasal ulceration, and serous otitis media. The presence of clinical signs such as suppurative otitis, mastoiditis, a saddle-nose defect, and hearing loss should alert the physician for GPA.
51 nursece4less.com nursece4less.com nursece4less.com nursece4less.com It has been shown that over 90% of patients with GPA have upper respiratory tract involvement. A large number of patients present with pulmonary symptoms (cough, hemoptysis, dyspnea and less commonly, pleuritic chest pain and tracheal obstruction). Bilateral or unilateral pulmonary infiltrates are present in nearly 50% of patients initially, with lung disease eventually developing in 85–90% of patients. Pleural effusion has also been reported in 12% of cases. GPA can cause significant morbidity and mortality secondary to diffuse pulmonary hemorrhage.203,206
Although renal involvement is clinically evident in only 11–20% of cases at presentation, glomerulonephritis eventually develops in 77–85% of patients, usually within the first two years of disease onset. Dermatologic involvement has been reported in about 50% of patients with GPA with purpura involving the lower extremities being the most common finding. Less commonly, ulcers, vesicles, papules, subcutaneous nodules and lesions resembling those of pyoderma may be seen. Arthralgia and myalgia are seen in 70% of patients. Nervous system involvement is seen in about one-third of patients with peripheral neuropathies being the most common. Cranial neuropathies, external ophthalmoplegia, seizures, cerebritis and stroke syndromes are also important findings. Diabetes insipidus may occur when granulomas extend from the sinuses into the pituitary gland. Cardiac involvement is rare, with pericarditis being the most frequent complications (6%).202,207
Symptoms
The onset of GPA/Wegener’s may be slow moving with few symptoms, or rapid and severe. About 90% of patients have symptoms of a ‘cold,’ ‘runny nose’ or sinusitis that fail to respond to the usual therapeutic measures and last considerably longer than normal upper respiratory tract infections.
52 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Not all patients with GPA/Wegener’s experience all symptoms, and the severity of the disease is also different for each patient. If any of the symptoms listed below persist, consider a possible diagnosis of GPA/Wegener’s and arrange to have a complete evaluation, including health history, physical exam, laboratory studies, including a urinalysis and an ANCA test.208,209
• arthritic joint pain
• blood in urine (which may or may not be indicated by a change in urine color)
• cough (with or without the presence of blood)
• fever
• inflammation of the ear with hearing problems
• inflammation of the eye with vision problems
• lack of energy
• loss of appetite
• nasal membrane ulcerations and crusting
• night sweats
• numbness of limbs
• pleuritis (inflammation of the lining of the lung)
• rash and/or skin sores
• saddle-nose deformity
• weakness, fatigue
• weight loss
The specific symptoms and severity of the symptoms associated with granulomatosis with polyangiitis vary greatly from one person to another. Indeed, granulomatosis with polyangiitis has been described affecting almost all organ systems of the body. In most people, the disorder affects the respiratory tract and the kidneys. Some people may have mild disease, while
53 nursece4less.com nursece4less.com nursece4less.com nursece4less.com others develop life-threatening complications. The disorder can develop slowly over many months or it can develop rapidly over several days. Because each person with granulomatosis with polyangiitis is unique, and the symptoms described below may or may not apply to a specific individual.194
Initial symptoms usually occur in the upper respiratory tract and resemble those associated with a severe common cold, including a persistent runny nose (rhinorrhea), nasal crusting and nasal obstruction or congestion. More serious symptoms include nosebleeds, ulcerations of the mucous membranes in the nose with secondary bacterial infection, sinus pain, inflammation of the sinuses (paranasal sinusitis), and hoarseness. Some affected individuals will develop a hole or tear in the wall (septum) dividing the nostrils, resulting in the collapse of the bridge of the nose, a condition called saddle nose. Affected individuals may also develop recurrent middle ear inflammation (otitis media), which, if untreated, may eventually result in hearing loss.201
Additional initial symptoms can include fever, general feeling of ill health (malaise), weakness and fatigue, joint paint (arthralgia), loss of appetite, and unintended weight loss. Sometimes, the upper airways are affected for years before other symptoms develop and, sometimes, granulomatosis with polyangiitis remains isolated in the upper airways and the rest of the body remains unaffected. This may be called localized or limited granulomatosis with polyangiitis.210
Many affected individuals will develop symptoms affecting the lungs. These symptoms include a persistent cough, episodes of coughing up of blood (hemoptysis), difficulty breathing, chest pain, inflammation of the thin membrane lining the outside of the lungs and the inside of the lungs
54 nursece4less.com nursece4less.com nursece4less.com nursece4less.com (pleuritis), and the excess buildup of fluid around the lungs (pleural effusion). There may be substances such as blood, pus or protein (pulmonary infiltrates) in lung tissue that can be detected on x-ray examination. Sometimes, affected individuals experience inflammation and narrowing of the area of the windpipe below the vocal cords (subglottis), a condition known as subglottic stenosis. Inflammation and narrowing of the whole windpipe (tracheal stenosis) can also occur. These conditions can cause difficulty breathing, high-pitched noisy breathing (stridor), wheezing, or voice changes. Hemorrhaging in the lungs is a potential serious complication that requires hospitalization and aggressive treatment.
Respiratory symptoms are often the first sign in children with this disorder. Approximately 75% of individuals eventually develop kidney disease. However, in many people, no symptoms are apparent. Affected individuals may develop high blood pressure and/or inflammation of the cluster of blood vessels and nerve fibers of the kidney called the glomeruli, which filter the blood. Glomeruli become swollen and misshapen and cannot perform their proper function, a condition known as glomerulonephritis. This can lead to small amounts of blood and protein in the urine. Without treatment, progressive kidney damage can occur, eventually causing life-threatening kidney failure.202,205
Most individuals experience symptoms affecting the muscles and skeleton, including pain in various joints (polyarthralgia), inflammation and swelling of the joints, inflammation of muscles (myositis), and muscle pain (myalgia). More than half of individuals with granulomatosis with polyangiitis experience ocular abnormalities, including conjunctivitis, corneal ulcerations, inflammation of the sclera of the eyeball (scleritis), and inflammation of the membrane covering the sclera (episcleritis). Affected individuals may also
55 nursece4less.com nursece4less.com nursece4less.com nursece4less.com develop an abnormal mass or sore behind the eye (orbital mass lesion or ‘pseudotumor’). Eye abnormalities may result in eye pain, redness, bulging or protrusion of the eyeballs (proptosis), double vision (diplopia), and vision loss. Additional findings can occur in some people. Sometimes, problems with the eyes are the first symptom of granulomatosis with polyangiitis.201
Approximately half of affected individuals develop skin abnormalities including small raised bumps (papules), slightly larger, deeper bumps just below the surface of the skin (subcutaneous nodules), skin ulcers, hemorrhage within skin layers, causing the appearance of small purplish spots on the skin (petechiae), and/or areas of purple discoloration caused by bleeding vessels near the surface of the skin (purpura). Skin lesions may or may not be painful. Some affected individuals may have painfully cold fingers and toes in response to cold (Raynaud’s phenomenon) caused by lack of blood flow to these areas. Sometimes, this is severe enough to cause tissue death (gangrene) of the tips of the fingers and toes.210
In rare instances, individuals may also develop neurological abnormalities including inflammation and degeneration of nerve fibers outside of the brain and spinal cord (peripheral neuropathy), injury to a few peripheral nerves in different areas simultaneously (mononeuritis multiplex), and inflammation of cranial nerves (cranial neuritis). Peripheral neuropathy can cause a sensation of numbness, burning or tingling in the hands or feet.
Mononeuritis multiplex can cause pain, weakness and abnormal sensations in the affected areas. The specific symptoms depended on which areas of the body are affected. Symptoms of cranial symptoms depend on which cranial nerves are affected. Headaches, seizures, and paralysis on one side of the body (hemiplegia) have also been reported.211
56 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Other rare symptoms include abnormalities of the heart including inflammation of the membranous sac that surrounds the heart (pericarditis), inflammation of the endocardium (endocarditis), which is the inner membrane lining of the heart, inflammation of the arteries that supply blood to the heart muscles (coronary arteritis), and disease of the heart muscle (cardiomyopathy). Some affected individuals may be at an increased risk of having a stroke or myocardial infarction.212
Causes
The exact cause of granulomatosis with polyangiitis is not fully understood. Because of the characteristic tissue changes seen in affected tissues, and increased immune response of the body, an immune reaction has been suggested as a possible basis for the disorder. Many researchers consider the disorder an autoimmune disorder. As mentioned earlier, an autoimmune disorder is when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.213
In granulomatosis with polyangiitis, white blood cells called neutrophils release abnormal immune proteins that can damage the body. Normally, neutrophils are instrumental in fighting off infection by surrounding and destroying bacteria that enter the body. About 85%-90% of people have antineutrophil cytoplasmic antibodies (ANCA). Of these people, about 80% have what is called cytoplasmic-ANCA, or c-ANCA. About 20% of those people have perinuclear-ANCA, or p-ANCA. Antibodies, or immunoglobulins, are specialized proteins that bind to invading or foreign substances in the body and bring about their destruction.
Autoantibodies are antibodies that mistakenly attack healthy tissue. The exact role these autoantibodies play in the development of granulomatosis
57 nursece4less.com nursece4less.com nursece4less.com nursece4less.com with polyangiitis is not fully understood. Many researchers believe that an infection ‘sets off’ the immune system causing it to malfunction. While many researchers believe that an infection contributes to the development of the disorder, it is unlikely that an infection alone can explain a disorder as complex as granulomatosis with polyangiitis. There are likely additional factors including environmental and genetic ones that also play a role in the development of the disorder. Research into this question is ongoing, but so far, no specific infectious, genetic, or environmental factor has been conclusively identified to be associated with the disorder.
The symptoms of granulomatosis with polyangiitis occur because of inflammation of the blood vessels. This inflammation leads to narrowing of the vessels and results in reduced blood flow to, and loss of tissue in, various organ systems of the body. The disorder is marked by the abnormal clumping or massing immune system cells that are produced to fight infection or inflammation. These clumps of cells, granulomas, can be found within various organ tissues and blood vessels of the body (granulomatosis).205,206
Diagnosis
The diagnosis of GPA is difficult and often delayed due to the wide range of clinical presentations. Historically, the diagnosis of GPA has been made following the criteria of granulomatous involvement of upper and lower respiratory tract, glomerulonephritis and varying degrees of systemic vasculitis. In an effort to diagnose GPA, Fauci and colleagues at the National Institute of Health (NIH) came up with definitive diagnostic criteria for GPA. According to these criteria, a patient should have clinical evidence of disease in at least two of three areas (upper airways, lung and kidney), and biopsy
58 nursece4less.com nursece4less.com nursece4less.com nursece4less.com results that show disease in at least one and preferably two of these organ systems.212
The American College of Rheumatology has established the following criteria for the diagnosis of GPA in order to distinguish the disease from other vasculitides: i) a urinary sediment containing red blood cell casts or more than five red blood cells per high-power field, ii) abnormal findings on the chest radiograph, iii) oral ulcers or nasal discharge and iv) granulomatous inflammation on biopsy. The presence of two or more of these four criteria was associated with an 88% sensitivity and 92% specificity.208,214
Another diagnostic system known as the ELK (E for ears, nose and throat or upper respiratory tract; L for lung; and K for kidney) classification system proposed by DeRemee and colleagues utilizes ANCA results. According to this system, any typical manifestation in the E, L or K supported by typical histopathology or a positive cytoplasmic ANCA (c-ANCA) test qualifies for the diagnosis of GPA. ANCA has been recognized to be both sensitive and specific for GPA and is highly associated with GPA, being present in 80–90% of patients with systemic disease. Still, there are some cases of the disease where ANCA is negative. Off all the ANCA associated with GPA, 80–95% of cases are associated with c-ANCA with autoantibodies directed against proteinase 3 antibodies (PR3) the remainder are p-ANCA directed against myeloperoxidase antibodies (MPO).202,205
In patients with limited form of the disease, ANCA is found in 50–80% of cases. In both limited and systemic GPA cases, PR3-ANCA is more common than MPO-ANCA. Whether ANCA-negative GPA represents a detection issue or different mechanisms that do not involve ANCA is yet to be known. GPA patients with MPO-ANCA tend to have less severe disease and a more
59 nursece4less.com nursece4less.com nursece4less.com nursece4less.com favorable course. Despite clinical remission, elevated ANCA titers may still persist in up to 40% of patients, and ANCA titer changes with disease activity in only 64% of patients. A recent study suggested that the presence of MPO-ANCA may be associated with more treatment resistance, and the presence of PR3-ANCA might be a predictor of disease relapse.206
Other laboratory findings at the time of diagnosis such as leukocytosis, anemia, and thrombocytosis are generally nonspecific. Although both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in patients with GPA, ESR correlates better with disease activity than does CRP. All immunoglobulins levels may be elevated, especially IgE. rheumatoid factor (RF) has been reported to be elevated in more than 50% of patients. The presence of abnormal urinary sediment, proteinuria, and abnormal creatinine clearance should raise the suspicion of glomerular involvement.199,215
Biopsy of orbital or ocular tissue can be performed. When reviewed, orbital biopsies in patients with GPA were found to have common elements that included changes in orbital fat (necrosis, lipid-laden macrophages and giant cells), micro abscesses, and granulomatous inflammation. Necrotizing vasculitis was uncommon. Typical findings on scleral biopsy include granulomatous foci, polymorphous inflammation (plasma cells, lymphocytes and neutrophils), collagen necrosis and vasculitis. Lung tissue is the most commonly biopsied site. A renal biopsy, may show a necrotizing glomerulonephritis.204,216 Radiologic evaluation of the lungs, trachea, sinuses and orbits can be used to identify additional areas of involvement (and potential biopsy sites).
60 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Treatment
The treatment of granulomatosis with polyangiitis is directed toward the specific symptoms that are apparent in each individual. Modern treatment has dramatically improved the life expectancy and reduced organ damage in patients with granulomatosis with polyangiitis. Treatment may require the coordinated efforts of a team of specialists. Pediatricians or primary care physicians, specialists who diagnose and treat lung disorders (pulmonologists), specialists who diagnose and treat disorders of the ear, nose and throat (otolaryngologists), specialists who diagnose and treat disorders of the immune system (immunologists), specialists who diagnose and treat disorders of the musculoskeletal system and autoimmune diseases (rheumatologists), specialists who diagnose and treat the kidneys (nephrologists), specialists who diagnose and treat skin disorders (dermatologists), specialists who diagnose and treat disorders of the central nervous system and the brain (neurologists), specialists who diagnose and treat heart disorders (cardiologists), and other health clinicians may need to systematically and comprehensively plan an affected child’s treatment.210,216,217
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the presence or absence of certain symptoms; specific organs affected, overall severity of the disorder, an individual’s age and general health, and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health team in careful consultation with the patient based upon the specifics of his/her case, including a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects, patient preference, and other appropriate factors.206
61 nursece4less.com nursece4less.com nursece4less.com nursece4less.com The treatment of granulomatosis with polyangiitis can be broken down into two stages – inducing a remission of symptoms and then maintaining the remission (maintenance therapy). In 2011, the Food and Drug Administration (FDA) approved the use of rituximab in conjunction with glucocorticoids for the treatment of individuals with granulomatosis with polyangiitis. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Glucocorticoids are steroid hormones that are important in the regulation of the metabolism of a form of sugar called glucose and the modulation of the body’s response to stress such as reducing inflammation.195,196
For many years, affected individuals were treated with a combination of glucocorticoid drugs that reduce inflammation such as prednisone and cytotoxic drugs that impede the abnormal growth (proliferation) of cells. Cytotoxic drugs contain chemicals that are toxic to certain cells in the body. These drugs are used to block the growth or replication of these cells. Cyclophosphamide is the most common cytotoxic drug used to treat granulomatosis with polyangiitis.
When using a combination of a cytotoxic drug with a glucocorticoid, the duration of therapy depends on an affected individual’s response. White blood cell (leukocyte) counts are closely monitored. Dosages are reduced gradually to prevent severe deficiency of white blood cells. Attempts should be made to discontinue cytotoxic therapy if symptoms of the disorder have been absent for three to six months. Cytotoxic therapy can be replaced with another drug such as azathioprine or mycophenolate mofetil. The possibility of kidney disease relapse is carefully monitored when reducing (tapering) medication dosage or discontinuing the drug. Methotrexate is another drug
62 nursece4less.com nursece4less.com nursece4less.com nursece4less.com used to treat granulomatosis with polyangiitis. Glucocorticoids with methotrexate are sometimes used to treat less severe disease. Generally, methotrexate, mycophenolate mofetil and azathioprine are less toxic than cyclophosphamide.207,211
After remission has been achieved, maintenance therapy may be required. This usually involves using azathioprine, methotrexate, or rituximab. Cyclophosphamide is usually not used for maintenance therapy due to toxicity. The dose of glucocorticoids is usually lowered in stages (tapered) as well. Regardless of which therapy is used to achieve remission and for maintenance therapy, affected individuals can experience a recurrence (relapse) of the disorder, which can be called a “flare”. Sometimes, a relapse may be triggered by an infection.
Some affected individuals may have progressive kidney damage, and the kidneys may no longer be able to perform their normal functions. This necessitates dialysis and eventually a kidney transplant. Dialysis is a procedure in which a machine is used to perform the kidney’s basic functions of fluid and waste removal. Kidney transplantation has been successful for kidney failure resulting from granulomatosis with polyangiitis.202
Antibiotics have been used to treat secondary bacterial infections sometimes associated with granulomatosis with polyangiitis. Trimethoprim- sulfamethoxazole is an antibiotic that has been effective in treating affected individuals, particularly those with only upper airway involvement. It is often used to reduce the possibility of a lung infection called Pneumocystis jiroveci pneumonia, especially when intensive immune suppressive therapy is needed to control the vasculitis.
63 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Surgical intervention for subglottic stenosis or tracheal stenosis to maintain the airways may be necessary in some people. Surgery can fix a saddle nose if the underlying vasculitis is not active.
Systemic Treatment
The average life expectancy for a patient with GPA without treatment is only 5 months, with a 1-year survival rate of less than 20%. It is a common misconception that the presence of an ocular manifestation in the absence of systemic manifestations represents a quiet disease. It should be noticed that ocular manifestations, particularly necrotizing scleritis, can be an indicator for both morbidity and mortality unless appropriate systemic treatment is initiated.195,212
The best treatment approach requires team collaboration between different medical specialties in order to cover the different organs involved by the disease. Because of the importance of systemic therapy, a brief overview of current regimens will be discussed. Historical systemic treatment included a variety of modalities such as antibiotics, chelating agents and local irradiation. None of these modalities were successful. Corticosteroid treatment was also tried and it has been shown that corticosteroid alone doubled the life expectancy to about 12 months with a 1-year survival of 34%. Adding cyclophosphamide to corticosteroid therapy altered the prognosis of the disease and resulted in remission and extension of the survival rate.
Once remission has been achieved, it is recommended that cyclophosphamide treatment to be continued for at least another year before tapering the medication. Both oral and intravenous cyclophosphamide, in combination with corticosteroids, have been used successfully with equal
64 nursece4less.com nursece4less.com nursece4less.com nursece4less.com effectiveness. Because of the significant toxicity associated with cyclophosphamide therapy, alternative maintenance therapies have been used. Azathioprine has shown some success, but it is less effective than cyclophosphamide and should only be considered in patients experiencing adverse side effects or when fertility concerns arise. Methotrexate has been used in patients with limited GPA, though it is less likely to achieve and sustain remission.
Recently, trials confirmed that B cell depletion with rituximab were comparable to cyclophosphamide as part of induction therapy for active ANCA-associated vasculitis and with possibly superior performance in relapsing disease. Rituximab is a monoclonal antibody that targets the CD20 antigen on B cells and clears circulating B cells from the circulation, without affecting plasma cells which may be important in disease relapse. Neutropenia may develop, for which the patient should be monitored. Studies on the long-term effectiveness of rituximab are still in progress. The rituximab in ANCA-Associated Vasculitis (RAVE study), a double-blind, randomized, multicenter trial, showed that rituximab is a non-inferior alternative to cyclophosphamide for induction. Following this, Holle, et al., reported that rituximab was effective for vasculitic manifestations refractory to cyclophosphamide but was less effective for granulomatous manifestations. There are case reports of success treatment with infliximab as an adjuvant therapy to cyclophosphamide and methotrexate in the treatment of two adults with necrotizing scleritis and one child with non- necrotizing scleritis.200,218
Other therapies demonstrating some efficacy for induction and/or maintenance of remission have included mycophenolate mofetil, plasmaphereses, cyclosporine, intravenous immunoglobulin (IVIG), and
65 nursece4less.com nursece4less.com nursece4less.com nursece4less.com protein A immunoadsorption. Trimethoprim-sulfamethoxazole has been reported to be beneficial in patients with the limited form of GPA, where there is no renal involvement. Given the success of rituximab in GPA, other B lymphocyte targeting medications are being under investigations. There is currently a clinical trial underway to determine if a monoclonal antibody against B Cell Activating Factor can prevent relapse. Therapies to modulate the memory T cell (Th17) pathway are in development, though no studies specific to GPA are yet in progress. Given the presumed role of T lymphocytes in granuloma formation, it remains hopeful that therapies directed against T lymphocytes may benefit patients with refractory orbital granulomatous inflammation. An inhibitor to the activated complement molecule c5a is being studied as an induction agent in patients with GPA.209,210,219
Local Corticosteroid Therapy
Local corticosteroid therapy can be used for the treatment of some non- vision threatening ocular manifestation of GPA such as conjunctivitis and episcleritis, with careful monitoring of severe ocular complications that might appear during the course of the disease. These complications such as scleritis, peripheral ulcerative keratitis (PUK), uveitis and retinal and optic nerve vasculitis usually fail to respond to local therapy alone and require the use of systemic immunosuppressive therapy as soon as possible. Of note, orbital granulomas are more prone to relapse and many authors have found that these granulomas may only be partially responsive to cyclophosphamide or rituximab. Of the 40 patients with orbital granulomas reported by Holle, et al., 41% of cases were refractory to cyclophosphamide induction. Despite intensive immunosuppression, 72% developed some form of visual impairment and 19% suffered blindness secondary to optic nerve compression.
66 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Surgery is of limited benefit and is reserved for grave situations. Orbital decompression with de-bulking of the granuloma can be done in cases of compressive optic neuropathy. In cases of severe pain and complete blindness, retro-bulbar alcohol injection or enucleation can be used as palliative measures. In cases of nasolacrimal duct obstruction, surgical creation of a new outflow (dacryocystorhinostomy) is required to bypass obstruction and relieve epiphoria for resolution of these symptoms, though it is not without risk. Postoperative wound necrosis and naso-cutaneous fistula have been reported. The rate of adverse events is improved with preoperative and postoperative control of the underlying disease.212,220
Necrotizing scleritis and PUK can progress with resultant globe perforation. At this point, conjunctival resection, Tectonic scleral grafting, and cyanoacrylate glue are all used as temporizing measures while the systemic disease is brought under control. Even after remission is achieved, patients with corneal or scleral thinning can perforate with minor trauma and the use of polycarbonate safety glasses are highly recommended. Cataract and glaucoma are common in patients with GPA and are secondary to the chronic inflammation and corticosteroid treatment rather than the GPA itself. It is recommended that no surgery should be done during active disease, and even when the patient is in remission, the patient needs to be monitored closely during the postoperative period.202,221,222
Remission
There is no cure for GPA/Wegener’s, but early diagnosis and proper treatment is effective in reducing the symptoms of the disease and improving the quality of life and life expectancy of patients who suffer from it. The disease can be brought into remission with complete absence of all signs of disease. Long-term remission can be induced and maintained with
67 nursece4less.com nursece4less.com nursece4less.com nursece4less.com medications, close management and regular lab tests to help monitor the disease. Treatment can produce symptom-free intervals of 5 to 20 years or more. Some patients will achieve a drug-free remission. However, relapses are common but can be caught at their earliest and most treatable stage, for most patients, by paying attention to patient symptoms and lab tests. Patients with GPA/Wegener’s who are in remission must not hesitate to see a physician if any GPA symptoms return or if they are not feeling well.206
Summary
There are many genetic diseases that directly or indirectly affect the kidneys. They include Alport syndrome, amyloidosis, Goodpasture syndrome, and granulomatosis with polyangiitis. Some inherited kidney conditions are relatively common, while others are rare syndromes. Inherited kidney conditions are often associated with multisystem complications, complicating the course of care for many patients and adversely affecting quality of life. Health problems associated with these conditions range from mild to severe. As these conditions progress, patients can continue to live productively for many years. Inherited kidney conditions are challenging to treat. Clinical studies and research identify new inherited kidney diseases and target treatments for them.
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68 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. The primary sign of ______is the appearance of blood in the urine (hematuria) early in life.
a. Alport syndrome b. amyloidosis c. Goodpasture syndrome d. Wegener granulomatosis
2. The most common form of Alport syndrome is
a. autosomal recessive Alport syndrome (ARAS) b. autosomal dominant form (ADAS) c. primary Goodpasture syndrome d. X-linked Alport syndrome (XLAS)
3. The cause of ______is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody).
a. Alport syndrome b. Wegener granulomatosis c. primary amyloidosis (AL) d. Goodpasture syndrome
4. The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the
a. COL4A5 gene. b. aggregation-prone serum protein. c. transthyretin gene. d. HLA-DPB1 gene.
5. True or False: By age 60, nearly 100% of untreated males with X- linked Alport syndrome (XLAS) develop kidney failure.
a. True b. False
69 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6. Females with ______usually do not develop kidney insufficiency until later in life, or not at all, but the risk increases as they grow older.
a. Goodpasture syndrome b. autosomal dominant form (ADAS) c. X-linked Alport syndrome (XLAS) d. autosomal recessive Alport syndrome (ARAS)
7. Females have two X chromosomes in their cells, but with Alport syndrome one of the X chromosomes is “turned off” or inactivated during development, a process called
a. recession. b. lyonization. c. randomization. d. mutation.
8. Females who have an Alport syndrome disease gene present on one X chromosome are heterozygous for that disorder, meaning
a. they have one abnormal and one normal copy of the gene. b. the mutant X is expressed in each tissue, leading to severe symptoms of the disorder. c. they will not develop the disease. d. inactivation is skewed in favor of the mutated chromosome.
9. Individuals with ______can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision.
a. Goodpasture syndrome b. Wegener granulomatosis c. Alport syndrome d. amyloidosis
10. True or False: A suspected diagnosis of X-linked Alport syndrome (XLAS may) be confirmed by skin biopsy.
a. True b. False
70 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11. Alport syndrome is treated based on its symptoms in the following manner(s):
a. kidney transplants are contraindicated because this disease is hereditary. b. using medications but they do not delay onset of kidney failure. c. using medications to delay the progression of kidney disease. d. All of the above
12. Approximately 50% of the people with secondary amyloidosis have ______as the underlying disease.
a. rheumatoid arthritis b. hearing loss c. hypertension d. anemia
13. All the hereditary amyloidoses follow autosomal dominant inheritance, which means that the presence of a mutated gene
a. is always from a gene change in the affected individual. b. is inherited from the father. c. must be inherited from both parents. d. from one parent can cause the disease.
14. With hereditary amyloidosis, the risk of passing the abnormal gene from an affected parent to an offspring
a. is zero since hereditary amyloidosis is a recessive genetic disorder. b. is 50% for each pregnancy. c. is greatest for male offspring. d. declines with each pregnancy.
15. A patient with recurrent episodes of coughing up of blood, dyspnea, and/or anemia, has symptoms associated with
a. primary amyloidosis. b. plasmacytosis. c. Goodpasture syndrome. d. Wegener granulomatosis.
71 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16. True or False: In primary amyloidosis, a low-grade plasmacytosis is usually present in the bone marrow, which leads to true multiple myeloma in these patients.
a. True b. False
17. Goodpasture syndrome is a rare autoimmune disorder characterized by excessive bleeding into the lungs (pulmonary hemorrhaging) and
a. rheumatoid arthritis. b. blood in the urine (hematuria). c. vasculitis (inflammation of the blood vessels in the kidneys). d. inflammation of the glomeruli of the kidneys (glomerulonephritis).
18. In Goodpasture syndrome, immune cells produce antibodies against a specific region of collagen that attack the collagen in the
a. bones and cartilage. b. skin. c. lungs and kidneys. d. peritoneal cavity.
19. Mild forms of Goodpasture syndrome may be treated with ______to suppress or hinder the effectiveness of the body's immune system.
a. immunosuppressive drugs b. antibiotics c. dialysis d. corticosteroids
20. True or False: Goodpasture syndrome patients treated with intravenous methylprednisolone is an effective treatment and it for infection.
a. True b. False
72 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21. A characteristic feature of granulomatosis with polyangiitis (GPA) is
a. hematuria. b. glomerulonephritis. c. oliguria. d. vasculitis.
22. In patients with ______, inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose).
a. granulomatosis with polyangiitis (GPA) b. primary amyloidosis c. plasmacytosis d. Goodpasture syndrome
23. The genetic basis of granulomatosis with polyangiitis (GPA) is
a. definitively linked to the HLA-DPB1 gene. b. linked to the COL4A5 gene. c. not well understood. d. definitively linked to the transthyretin (TTR) gene.
24. True or False: Granulomatosis with polyangiitis (GPS) is specific in that it affects the respiratory tract and the kidneys and not the other organs of the body.
a. True b. False
25. In 2011, the Food and Drug Administration (FDA) approved the use of ______in conjunction with glucocorticoids for the treatment of individuals with granulomatosis with polyangiitis.
a. rituximab b. tafamidis c. patisiran d. revusiran
73 nursece4less.com nursece4less.com nursece4less.com nursece4less.com CORRECT ANSWERS:
1. The primary sign of ______is the appearance of blood in the urine (hematuria) early in life.
a. Alport syndrome
“The hallmark of [Alport syndrome] is the appearance of blood in the urine (hematuria) early in life, with progressive decline in kidney function (kidney insufficiency) that ultimately results in kidney failure, especially in affected males.”
2. The most common form of Alport syndrome is
d. X-linked Alport syndrome (XLAS)
“X-linked Alport syndrome (XLAS) is the most common; in these families affected males typically have more severe disease than affected females. In autosomal recessive Alport syndrome (ARAS) the severity of disease in affected males and females is similar. There is also an autosomal dominant form (ADAS) that affects males and females with equal severity.”
3. The cause of ______is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody).
c. primary amyloidosis (AL)
“The cause of AL (primary amyloidosis) is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (part of an antibody).”
4. The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the
c. transthyretin gene.
“The most common form of hereditary amyloidosis is caused by an abnormality (mutation) in the gene for transthyretin.”
74 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5. True or False: By age 60, nearly 100% of untreated males with X- linked Alport syndrome (XLAS) develop kidney failure.
a. True
“About 50% of untreated males with XLAS develop kidney failure by age 25, increasing to 90% by age 40 and nearly 100% by age 60.”
6. Females with ______usually do not develop kidney insufficiency until later in life, or not at all, but the risk increases as they grow older.
c. X-linked Alport syndrome (XLAS)
“Females with XLAS usually do not develop kidney insufficiency until later in life. They may not develop kidney insufficiency or failure at all, but the risk increases as they grow older.”
7. Females have two X chromosomes in their cells, but with Alport syndrome one of the X chromosomes is “turned off” or inactivated during development, a process called
b. lyonization.
“Females have two X chromosomes in their cells, but one of the X chromosomes is ‘turned off’ or inactivated during development, a process termed ‘lyonization,’ and all of the genes on that chromosome are inactivated.”
8. Females who have an Alport syndrome disease gene present on one X chromosome are heterozygous for that disorder, meaning
a. they have one abnormal and one normal copy of the gene.
“Females who have a disease gene present on one X chromosome are heterozygous for that disorder, meaning they have one abnormal copy of the gene and one normal copy. As the result of the lyonization process, most heterozygous females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.... If the normal copy prevails, then heterozygous females can be and remain completely asymptomatic. If the mutant copy prevails, then heterozygous females can be affected as severely as males.”
75 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. Individuals with ______can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision.
c. Alport syndrome
“Individuals with Alport syndrome can also develop progressive hearing loss of varying severity and abnormalities of the eyes that usually do not result in impaired vision.”
10. True or False: A suspected diagnosis of X-linked Alport syndrome (XLAS may) be confirmed by skin biopsy.
a. True
“When genetic testing is unavailable or inaccessible, studies of tissue specimens (biopsies) are performed. A suspected diagnosis of XLAS may be confirmed by skin biopsy.”
11. Alport syndrome is treated based on its symptoms in the following manner(s):
c. using medications to delay the progression of kidney disease.
“Alport syndrome is treated symptomatically and certain medications can potentially delay the progression of kidney disease and the onset of kidney failure. Ultimately, in many patients, a kidney transplant is required.”
12. Approximately 50% of the people with secondary amyloidosis have ______as the underlying disease.
a. rheumatoid arthritis
“Approximately 50% of the people with secondary amyloidosis have rheumatoid arthritis as the underlying disease.”
76 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13. All the hereditary amyloidoses follow autosomal dominant inheritance, which means that the presence of a mutated gene
d. from one parent can cause the disease.
“Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother. All the hereditary amyloidoses follow autosomal dominant inheritance, which means that the presence of one copy of a mutated gene can cause the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual.”
14. With hereditary amyloidosis, the risk of passing the abnormal gene from an affected parent to an offspring
b. is 50% for each pregnancy.
“The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females; however, not every person getting the gene will get sick with amyloidosis.”
15. A patient with recurrent episodes of coughing up of blood, dyspnea, and/or anemia, has symptoms associated with
c. Goodpasture syndrome.
“Symptoms of Goodpasture syndrome include recurrent episodes of coughing up of blood (hemoptysis), difficulty breathing (dyspnea), fatigue, chest pain, and/or abnormally low levels of circulating red blood cells (anemia).”
16. True or False: In primary amyloidosis, a low-grade plasmacytosis is usually present in the bone marrow, which leads to true multiple myeloma in these patients.
b. False
“Primary amyloidosis: ... Usually, a low-grade plasmacytosis is present in the bone marrow, which is similar to that in multiple myeloma, although most patients do not have true multiple myeloma (with lytic bone lesions, hypercalcemia, renal tubular casts, and anemia).”
77 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17. Goodpasture syndrome is a rare autoimmune disorder characterized by excessive bleeding into the lungs (pulmonary hemorrhaging) and
d. inflammation of the glomeruli of the kidneys (glomerulonephritis).
“Goodpasture syndrome is a rare autoimmune disorder characterized by inflammation of the filtering structures (glomeruli) of the kidneys (glomerulonephritis) and excessive bleeding into the lungs (pulmonary hemorrhaging).”
18. In Goodpasture syndrome, immune cells produce antibodies against a specific region of collagen that attack the collagen in the
c. lungs and kidneys.
“In Goodpasture syndrome, immune cells produce antibodies against a specific region of collagen. The antibodies attack the collagen in the lungs and kidneys.”
19. Mild forms of Goodpasture syndrome may be treated with ______to suppress or hinder the effectiveness of the body's immune system.
a. immunosuppressive drugs
“Mild forms of Goodpasture syndrome may be treated with the use of drugs that suppress or hinder the effectiveness of the body's immune system (immunosuppressive drugs).”
20. True or False: Goodpasture syndrome patients treated with intravenous methylprednisolone is an effective treatment and it for infection.
b. False
“Some patients have been treated with intravenous methylprednisolone, but there is no convincing evidence that it confers a benefit, and it may be associated with a greater risk for infection.”
78 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21. A characteristic feature of granulomatosis with polyangiitis (GPA) is
d. vasculitis.
“A characteristic feature of GPA is inflammation of blood vessels (vasculitis), particularly the small- and medium-sized blood vessels in the lungs, nose, sinuses, windpipe, and kidneys, although vessels in any organ can be involved.”
22. In patients with ______, inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose).
a. granulomatosis with polyangiitis (GPA)
“In most people with GPA, inflammation begins in the vessels of the respiratory tract, leading to nasal congestion, frequent nosebleeds, shortness of breath, or coughing. Severe inflammation in the nose can lead to a hole in the tissue that separates the two nostrils (nasal septum perforation) or a collapse of the septum, causing a sunken bridge of the nose (saddle nose).”
23. The genetic basis of granulomatosis with polyangiitis (GPA) is
c. not well understood.
“The genetic basis of GPA is not well understood. Having a particular version of the HLA-DPB1 gene is the strongest genetic risk factor for developing this condition, although several other genes, some of which have not been identified, may be involved. It is likely that a combination of genetic and environmental factors lead to GPA.”
24. True or False: Granulomatosis with polyangiitis (GPS) is specific in that it affects the respiratory tract and the kidneys and not the other organs of the body.
b. False
“Indeed, granulomatosis with polyangiitis has been described affecting almost all organ systems of the body. In most people, the disorder affects the respiratory tract and the kidneys.”
79 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25. In 2011, the Food and Drug Administration (FDA) approved the use of ______in conjunction with glucocorticoids for the treatment of individuals with granulomatosis with polyangiitis.
a. rituximab
“In 2011, the Food and Drug Administration (FDA) approved the use of rituximab (Rituxan®) in conjunction with glucocorticoids for the treatment of individuals with granulomatosis with polyangiitis.”
Reference Section
The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. [References are for a multi-part series on Common And Uncommon Kidney Diseases].
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