The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Epidemiology
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Anatomy
Pathophysiology
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Etiology
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
Genetics
Prognostic Factors
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Age group
Associated comorbidity
Associated activity
Acuity of presentation
Differential Diagnoses
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Laboratory Studies
Imaging Studies
Procedures
Histologic Findings
Staging
Treatment Paradigm
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
Healthy Diet: Encourage a balanced diet low in salt, saturated fats, and processed foods. A renal dietitian can help create a meal plan that supports kidney health, managing blood pressure, and minimizing proteinuria.Â
Hydration: Drink plenty of water to ensure adequate hydration unless otherwise advised by a healthcare provider due to specific kidney issues.Â
Regular Exercise: Encourage regular, moderate exercise to maintain overall health and manage weight. Activities should be tailored to individual capabilities and consider any physical limitations caused by the condition.Â
Avoiding Nephrotoxic Substances: Individuals with alport syndrome should avoid substances that can harm the kidneys, such as excessive non-prescribed medications (especially NSAIDs), and nephrotoxic substances like certain dyes or contrast agents.Â
Hearing Protection: As alport syndrome can lead to hearing loss, especially in males, it’s essential to protect the ears from loud noises. Using earplugs or earmuffs in loud environments can help prevent further damage.Â
Regular Monitoring and Check-ups: Regular visits to healthcare professionals, including nephrologists, ophthalmologists, and audiologists, are crucial for monitoring kidney function, eye health, and hearing status.Â
Blood Pressure Management: Given that high blood pressure can accelerate kidney damage in alport syndrome, monitoring and managing blood pressure levels with medications and lifestyle modifications are essential.Â
Avoiding Smoking and Alcohol: Both smoking and excessive alcohol consumption can exacerbate kidney damage, so individuals with alport syndrome should avoid or minimize these habits.Â
Emotional Support: Alport Syndrome can have significant emotional and psychological impacts due to its chronic nature. Seeking support through counselling, support groups, or therapy can help individuals cope with the challenges.Â
Education and Awareness: Educating oneself and family members about alport syndrome helps in understanding the condition, managing its symptoms, and making informed decisions about treatment and lifestyle.Â
Effectiveness of ACE inhibitor in treating alport Syndrome
Enalapril acts as a competitive inhibitor of ACE. Its mechanism involves blocking the conversion of angiotensin I to angiotensin II, a powerful vasoconstrictor. This action leads to elevated levels of plasma renin and a decrease in aldosterone secretion.Â
ACE inhibitors like fosinopril work by dilating blood vessels, which can help reduce blood pressure and decrease the amount of work the heart must do. In the context of kidney conditions like alport syndrome, ACE inhibitors are often used to help manage proteinuria (the presence of excess proteins in the urine) and to slow down the progression of kidney damage.Â
cyclosporine, a cyclic polypeptide, functions by inhibiting certain aspects of humoral immunity and, to a larger degree, cell-mediated immune responses.Â
Losartan, an angiotensin receptor blocker (ARB), has shown promise in managing alport syndrome, a genetic kidney disorder characterized by kidney disease, hearing loss, and eye abnormalities.Â
Losartan is a viable option for patients who cannot endure ACE inhibitors.Â
candesartan (Atacand) Candesartan is a viable option for individuals who cannot tolerate ACE inhibitors. It operates as a nonpeptide antagonist of the angiotensin II receptor, effectively hindering the vasoconstrictive and aldosterone-secreting impacts of angiotensin II.Â
Valsartan is a suitable option for individuals who cannot tolerate ACE inhibitors. It has the potential to inhibit the RAAS more effectively and comprehensively than ACE inhibitors. Moreover, it doesn’t impact the reaction to bradykinin and is less prone to causing cough and angioedema.Â
Kidney Transplant: In cases where alportsyndrome leads to end-stage renal disease (ESRD), a kidney transplant may be considered. This involves the surgical replacement of a failed kidney with a healthy donor kidney. Before a transplant, patients typically undergo extensive evaluation to ensure their suitability for the surgery and the post-transplant recovery process.Â
role-of-management-in-treating-alport-syndrome
Diagnosis and Evaluation: Accurate diagnosis is essential. This involves a thorough medical history, physical examination, and specialized tests such as kidney function tests, hearing tests, eye exams, and genetic testing to confirm the presence of alport syndrome and assess its severity.Â
Monitoring and Regular Follow-ups: Continuous monitoring is crucial to track the progression of the disease and its impact on various organs. Regular follow-ups with healthcare providers, including nephrologists, ophthalmologists, and audiologists, are necessary to manage and address emerging symptoms or complications.Â
Treatment and Symptom Management: There is no cure for alport syndrome, but treatments aim to manage symptoms, slow down kidney damage, and alleviate associated conditions. Treatment may involve:Â
Blood pressure controlÂ
Dietary modifications (low salt and protein)Â
Medications to manage proteinuria and delay kidney damageÂ
Hearing aids for hearing lossÂ
Corrective lenses for vision problemsÂ
Supportive Care: Providing support and guidance to individuals and families affected by alport syndrome is crucial. Â
Genetic Counseling: Offering genetic counseling is vital, especially for families affected by alport syndrome. This involves discussing inheritance patterns, the likelihood of passing the condition to future generations, and available reproductive options or prenatal testing for families considering having children.Â
Research and Clinical Trials: Participating in or supporting research efforts and clinical trials helps advance understanding, discover potential treatments, and improve the management of alport syndrome. Encouraging affected individuals to engage in research or clinical trials can provide them with access to cutting-edge treatments and therapies.Â
Transitional Care: As patients with alport syndrome transition from pediatric to adult care, a structured plan must ensure a smooth transition. This includes coordination between pediatric and adult healthcare providers, educating patients about managing their condition independently, and addressing any specific concerns related to transitioning care.Â
End-Stage Kidney Disease Management: For individuals who progress to end-stage kidney disease, renal replacement therapy options such as dialysis or kidney transplantation become necessary. Proper evaluation, preparation, and ongoing care are essential for those undergoing these treatments.Â
The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
Healthy Diet: Encourage a balanced diet low in salt, saturated fats, and processed foods. A renal dietitian can help create a meal plan that supports kidney health, managing blood pressure, and minimizing proteinuria.Â
Hydration: Drink plenty of water to ensure adequate hydration unless otherwise advised by a healthcare provider due to specific kidney issues.Â
Regular Exercise: Encourage regular, moderate exercise to maintain overall health and manage weight. Activities should be tailored to individual capabilities and consider any physical limitations caused by the condition.Â
Avoiding Nephrotoxic Substances: Individuals with alport syndrome should avoid substances that can harm the kidneys, such as excessive non-prescribed medications (especially NSAIDs), and nephrotoxic substances like certain dyes or contrast agents.Â
Hearing Protection: As alport syndrome can lead to hearing loss, especially in males, it’s essential to protect the ears from loud noises. Using earplugs or earmuffs in loud environments can help prevent further damage.Â
Regular Monitoring and Check-ups: Regular visits to healthcare professionals, including nephrologists, ophthalmologists, and audiologists, are crucial for monitoring kidney function, eye health, and hearing status.Â
Blood Pressure Management: Given that high blood pressure can accelerate kidney damage in alport syndrome, monitoring and managing blood pressure levels with medications and lifestyle modifications are essential.Â
Avoiding Smoking and Alcohol: Both smoking and excessive alcohol consumption can exacerbate kidney damage, so individuals with alport syndrome should avoid or minimize these habits.Â
Emotional Support: Alport Syndrome can have significant emotional and psychological impacts due to its chronic nature. Seeking support through counselling, support groups, or therapy can help individuals cope with the challenges.Â
Education and Awareness: Educating oneself and family members about alport syndrome helps in understanding the condition, managing its symptoms, and making informed decisions about treatment and lifestyle.Â
Enalapril acts as a competitive inhibitor of ACE. Its mechanism involves blocking the conversion of angiotensin I to angiotensin II, a powerful vasoconstrictor. This action leads to elevated levels of plasma renin and a decrease in aldosterone secretion.Â
ACE inhibitors like fosinopril work by dilating blood vessels, which can help reduce blood pressure and decrease the amount of work the heart must do. In the context of kidney conditions like alport syndrome, ACE inhibitors are often used to help manage proteinuria (the presence of excess proteins in the urine) and to slow down the progression of kidney damage.Â
cyclosporine, a cyclic polypeptide, functions by inhibiting certain aspects of humoral immunity and, to a larger degree, cell-mediated immune responses.Â
Losartan, an angiotensin receptor blocker (ARB), has shown promise in managing alport syndrome, a genetic kidney disorder characterized by kidney disease, hearing loss, and eye abnormalities.Â
Losartan is a viable option for patients who cannot endure ACE inhibitors.Â
candesartan (Atacand) Candesartan is a viable option for individuals who cannot tolerate ACE inhibitors. It operates as a nonpeptide antagonist of the angiotensin II receptor, effectively hindering the vasoconstrictive and aldosterone-secreting impacts of angiotensin II.Â
Valsartan is a suitable option for individuals who cannot tolerate ACE inhibitors. It has the potential to inhibit the RAAS more effectively and comprehensively than ACE inhibitors. Moreover, it doesn’t impact the reaction to bradykinin and is less prone to causing cough and angioedema.Â
Kidney Transplant: In cases where alportsyndrome leads to end-stage renal disease (ESRD), a kidney transplant may be considered. This involves the surgical replacement of a failed kidney with a healthy donor kidney. Before a transplant, patients typically undergo extensive evaluation to ensure their suitability for the surgery and the post-transplant recovery process.Â
Diagnosis and Evaluation: Accurate diagnosis is essential. This involves a thorough medical history, physical examination, and specialized tests such as kidney function tests, hearing tests, eye exams, and genetic testing to confirm the presence of alport syndrome and assess its severity.Â
Monitoring and Regular Follow-ups: Continuous monitoring is crucial to track the progression of the disease and its impact on various organs. Regular follow-ups with healthcare providers, including nephrologists, ophthalmologists, and audiologists, are necessary to manage and address emerging symptoms or complications.Â
Treatment and Symptom Management: There is no cure for alport syndrome, but treatments aim to manage symptoms, slow down kidney damage, and alleviate associated conditions. Treatment may involve:Â
Blood pressure controlÂ
Dietary modifications (low salt and protein)Â
Medications to manage proteinuria and delay kidney damageÂ
Hearing aids for hearing lossÂ
Corrective lenses for vision problemsÂ
Supportive Care: Providing support and guidance to individuals and families affected by alport syndrome is crucial. Â
Genetic Counseling: Offering genetic counseling is vital, especially for families affected by alport syndrome. This involves discussing inheritance patterns, the likelihood of passing the condition to future generations, and available reproductive options or prenatal testing for families considering having children.Â
Research and Clinical Trials: Participating in or supporting research efforts and clinical trials helps advance understanding, discover potential treatments, and improve the management of alport syndrome. Encouraging affected individuals to engage in research or clinical trials can provide them with access to cutting-edge treatments and therapies.Â
Transitional Care: As patients with alport syndrome transition from pediatric to adult care, a structured plan must ensure a smooth transition. This includes coordination between pediatric and adult healthcare providers, educating patients about managing their condition independently, and addressing any specific concerns related to transitioning care.Â
End-Stage Kidney Disease Management: For individuals who progress to end-stage kidney disease, renal replacement therapy options such as dialysis or kidney transplantation become necessary. Proper evaluation, preparation, and ongoing care are essential for those undergoing these treatments.Â
The syndrome was first described by a British physician in 1927 and was named after him in 1961. Alport syndrome is an X-linked genetic disorder caused by mutations in the genes encoding type 4 collagen. It can also be transmitted in an autosomal recessive, or autosomal dominant pattern.
The most common symptom is hematuria, and males are more commonly affected than females. The disease is characterized by renal failure, hearing loss, and eye abnormalities and can lead to proteinuria, hypertension, progressive loss of kidney function, and end-stage renal disease.
Alport syndrome is a rare genetic disorder that affects around 1 in 50,000 newborns, with males being more commonly affected than females. It is estimated that 30,000 to 60,000 people in the United States are affected by this disorder, accounting for approximately 2.2% of children and 0.2% of adults with end-stage renal disease (ESRD).
The X-linked form of Alport syndrome is the most common type. Alport syndrome is a significant cause of chronic kidney disease and ESRD in young adults, accounting for 1.5% to 3.0% of children on renal replacement therapies in the US and Europe.
Alport syndrome is a genetic disorder caused by mutations in the COL4A3 and COL4A4 genes, which affect the production and accumulation of collagen 4 α3, α4, and α5 network in the basement membranes of the glomerulus, cochlea, and eye. XLAS (X-linked Alport syndrome) is caused by mutations in both alleles of the COL4A5 gene, while ADAS (autosomal dominant Alport syndrome) and ARAS (autosomal recessive Alport syndrome) are caused by mutations in one allele of either the COL4A3 or COL4A4 gene.
ADAS is common, and patients have a slower progression of kidney disease and fewer extra-renal manifestations than those with XLAS. The primary pathology in Alport syndrome is in the noncollagenous (NC1) C-terminal of the alpha-5 chain in XLAS and alpha-3 or alpha-4 chains in ADAS and ARAS. In kidney development, the glomerular basement membrane primarily consists of alpha-1 and alpha-2 collagen chains. As the kidneys mature, a unique collagen network formed by alpha-3, alpha-4, and alpha-5 chains takes over.
Alport Syndrome is caused by a defect in any of these chains, while X-Linked Alport Syndrome (XLAS) specifically results from an arrested developmental switch of type IV collagen, which leads to the persistent presence of alpha-1 and alpha-2 chains and the absence of alpha-3, alpha-4, and alpha-5. This causes the GBM to be more vulnerable to proteolytic enzymes, resulting in damage and splitting. Anti-GBM nephritis occurs when circulating antibodies bind to specific collagen chains in the kidneys. In ARAS, the antibodies bind to the alpha-3 and alpha-4 chains, while in XLAS, they target the alpha-5 chain.
Alport syndrome is a genetic disorder caused by mutations in the genes responsible for type IV collagen’s alpha-3, alpha-4, and alpha-5 chains. The most common type is X-linked Alport syndrome (XLAS), which accounts for about 85% of cases and is caused by mutations in the COL4A5 gene. These mutations can be minor, such as splice-site mutations, missense mutations, or larger deletions.
About 20% of mutations in the COL4A5 gene are large or medium-sized deletions. The combination of XLAS and leiomyomatosis of the esophagus, female genital tract, and the tracheobronchial tree can also be caused by a specific deletion involving the COL4A5 and COL4A6 genes. There are also rarer forms of Alport syndrome, such as ARAS and ADAS, which are caused by mutations in the COL4A3 or COL4A4 gene.
These mutations include frameshift deletions, amino acid substitutions, missense mutations, splicing mutations, and in-frame deletions. Only six mutations in the COL4A3 gene and twelve in the COL4A4 gene have been seen in patients with ARAS. Alport syndrome can cause hearing loss, kidney disease, and eye abnormalities.
The prognosis for X-linked Alport syndrome is worst for males, with about 50% requiring dialysis or transplantation by 30 years and 90% developing the end-stage renal disease by 40. Females with X-linked Alport syndrome have a better prognosis, with 12% developing ESRD by age 40, but still have a significant risk of renal morbidity and hearing impairment.
The rate of ESRD increases to 30% by age 60 and approaches 40% by age 80. In contrast, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20, while the autosomal dominant form typically delays ESRD until middle age.
Clinical History
Individuals with Alport syndrome may develop hematuria, proteinuria, edema, hypertension, and end-stage renal disease (ESRD). They may also experience hearing loss and ocular abnormalities, including cone-shaped lenses, cataracts, retinal pigmentary changes, and corneal erosions. These symptoms typically worsen, with ESRD developing between the ages of 16 and 35.
Hearing loss usually appears in late childhood or early adolescence, before the onset of kidney failure, and usually starts with high-frequency loss. These symptoms worsen over time and typically appear in late childhood or adolescence. Alport syndrome often causes sensorineural hearing loss.
This hearing loss is not present at birth and typically begins in late childhood or early adolescence before kidney failure occurs. Hearing loss is always linked to kidney involvement. About 50% of male patients with Alport syndrome will have sensorineural hearing impairment by age 25, and about 90% will be completely deaf by age 40.
Physical Examination
Around 60-70% of patients have episodes of gross hematuria, usually triggered by upper respiratory infections, in the first two decades of life. If there is no hematuria in a male patient in the first decade of life, it is less likely that they have Alport syndrome. Proteinuria is generally absent in childhood but develops in males with XLAS and male and female patients with ARAS. The incidence and severity of symptoms increase with age and the extent of kidney failure.
Hypertension, edema, and nephrotic syndrome develop by the second decade of life. Chronic anemia and osteodystrophy may manifest as kidney insufficiency progresses. Alport syndrome is the most common cause of dot-and-fleck retinopathy, a condition where numerous white and yellow dots and flecks develop around the macula in around 85% of males with XLAS.
It typically appears at the onset of kidney failure and is usually asymptomatic. Posterior polymorphous corneal dystrophy is a rare manifestation of Alport syndrome, which appears as clear vesicles on the endothelial surface of the cornea. It is generally bilateral but can be unilateral, and most people are asymptomatic, but some may experience visual impairment.
Differential Diagnoses
Acute post-streptococcal glomerulonephritis
Immunoglobulin A nephropathy
Medullary cystic disease
Multicystic renal dysplasia
Polycystic kidney disease
Thin GBM disease
Alport Syndrome does not have a specific treatment, but treatments are available to limit the progression of proteinuria and kidney disease. This includes using medications such as ACEi and ARBs to manage hypertension, CKD, and proteinuria, as well as diuretics, depending on the level of proteinuria. Although the treatment may delay the onset of renal impairment, most people affected by Alport will ultimately require dialysis or a kidney transplant.
Research has suggested that combination therapy of an ARB/ACE inhibitor, a statin, and a non-dihydropyridine calcium channel blocker can safely improve hypertension, albuminuria, lipid abnormalities, and glomerular selectivity also stop the progression of ESRD in those without renal insufficiency. Women with Alport syndrome have a higher risk of pregnancy complications such as proteinuria, renal insufficiency, hypertension, and preeclampsia, particularly in those with pre-existing renal insufficiency, proteinuria, or hypertension and require the involvement of a nephrologist and high-risk obstetrics for optimal maternal and fetal outcomes.
The best time to determine genetic risk and discuss genetic testing options is before pregnancy. For X-linked or autosomal recessive conditions, it is appropriate to offer genetic counseling to individuals who are affected, is carriers, or are at risk of being carriers. Additionally, it is recommended to consider DNA banking for individuals with undiagnosed conditions, as future advances in testing and understanding of genetics may provide new insights.
Healthy Diet: Encourage a balanced diet low in salt, saturated fats, and processed foods. A renal dietitian can help create a meal plan that supports kidney health, managing blood pressure, and minimizing proteinuria.Â
Hydration: Drink plenty of water to ensure adequate hydration unless otherwise advised by a healthcare provider due to specific kidney issues.Â
Regular Exercise: Encourage regular, moderate exercise to maintain overall health and manage weight. Activities should be tailored to individual capabilities and consider any physical limitations caused by the condition.Â
Avoiding Nephrotoxic Substances: Individuals with alport syndrome should avoid substances that can harm the kidneys, such as excessive non-prescribed medications (especially NSAIDs), and nephrotoxic substances like certain dyes or contrast agents.Â
Hearing Protection: As alport syndrome can lead to hearing loss, especially in males, it’s essential to protect the ears from loud noises. Using earplugs or earmuffs in loud environments can help prevent further damage.Â
Regular Monitoring and Check-ups: Regular visits to healthcare professionals, including nephrologists, ophthalmologists, and audiologists, are crucial for monitoring kidney function, eye health, and hearing status.Â
Blood Pressure Management: Given that high blood pressure can accelerate kidney damage in alport syndrome, monitoring and managing blood pressure levels with medications and lifestyle modifications are essential.Â
Avoiding Smoking and Alcohol: Both smoking and excessive alcohol consumption can exacerbate kidney damage, so individuals with alport syndrome should avoid or minimize these habits.Â
Emotional Support: Alport Syndrome can have significant emotional and psychological impacts due to its chronic nature. Seeking support through counselling, support groups, or therapy can help individuals cope with the challenges.Â
Education and Awareness: Educating oneself and family members about alport syndrome helps in understanding the condition, managing its symptoms, and making informed decisions about treatment and lifestyle.Â
Enalapril acts as a competitive inhibitor of ACE. Its mechanism involves blocking the conversion of angiotensin I to angiotensin II, a powerful vasoconstrictor. This action leads to elevated levels of plasma renin and a decrease in aldosterone secretion.Â
ACE inhibitors like fosinopril work by dilating blood vessels, which can help reduce blood pressure and decrease the amount of work the heart must do. In the context of kidney conditions like alport syndrome, ACE inhibitors are often used to help manage proteinuria (the presence of excess proteins in the urine) and to slow down the progression of kidney damage.Â
cyclosporine, a cyclic polypeptide, functions by inhibiting certain aspects of humoral immunity and, to a larger degree, cell-mediated immune responses.Â
Losartan, an angiotensin receptor blocker (ARB), has shown promise in managing alport syndrome, a genetic kidney disorder characterized by kidney disease, hearing loss, and eye abnormalities.Â
Losartan is a viable option for patients who cannot endure ACE inhibitors.Â
candesartan (Atacand) Candesartan is a viable option for individuals who cannot tolerate ACE inhibitors. It operates as a nonpeptide antagonist of the angiotensin II receptor, effectively hindering the vasoconstrictive and aldosterone-secreting impacts of angiotensin II.Â
Valsartan is a suitable option for individuals who cannot tolerate ACE inhibitors. It has the potential to inhibit the RAAS more effectively and comprehensively than ACE inhibitors. Moreover, it doesn’t impact the reaction to bradykinin and is less prone to causing cough and angioedema.Â
Kidney Transplant: In cases where alportsyndrome leads to end-stage renal disease (ESRD), a kidney transplant may be considered. This involves the surgical replacement of a failed kidney with a healthy donor kidney. Before a transplant, patients typically undergo extensive evaluation to ensure their suitability for the surgery and the post-transplant recovery process.Â
Diagnosis and Evaluation: Accurate diagnosis is essential. This involves a thorough medical history, physical examination, and specialized tests such as kidney function tests, hearing tests, eye exams, and genetic testing to confirm the presence of alport syndrome and assess its severity.Â
Monitoring and Regular Follow-ups: Continuous monitoring is crucial to track the progression of the disease and its impact on various organs. Regular follow-ups with healthcare providers, including nephrologists, ophthalmologists, and audiologists, are necessary to manage and address emerging symptoms or complications.Â
Treatment and Symptom Management: There is no cure for alport syndrome, but treatments aim to manage symptoms, slow down kidney damage, and alleviate associated conditions. Treatment may involve:Â
Blood pressure controlÂ
Dietary modifications (low salt and protein)Â
Medications to manage proteinuria and delay kidney damageÂ
Hearing aids for hearing lossÂ
Corrective lenses for vision problemsÂ
Supportive Care: Providing support and guidance to individuals and families affected by alport syndrome is crucial. Â
Genetic Counseling: Offering genetic counseling is vital, especially for families affected by alport syndrome. This involves discussing inheritance patterns, the likelihood of passing the condition to future generations, and available reproductive options or prenatal testing for families considering having children.Â
Research and Clinical Trials: Participating in or supporting research efforts and clinical trials helps advance understanding, discover potential treatments, and improve the management of alport syndrome. Encouraging affected individuals to engage in research or clinical trials can provide them with access to cutting-edge treatments and therapies.Â
Transitional Care: As patients with alport syndrome transition from pediatric to adult care, a structured plan must ensure a smooth transition. This includes coordination between pediatric and adult healthcare providers, educating patients about managing their condition independently, and addressing any specific concerns related to transitioning care.Â
End-Stage Kidney Disease Management: For individuals who progress to end-stage kidney disease, renal replacement therapy options such as dialysis or kidney transplantation become necessary. Proper evaluation, preparation, and ongoing care are essential for those undergoing these treatments.Â
Both our subscription plans include Free CME/CPD AMA PRA Category 1 credits.
Digital Certificate PDF
On course completion, you will receive a full-sized presentation quality digital certificate.
medtigo Simulation
A dynamic medical simulation platform designed to train healthcare professionals and students to effectively run code situations through an immersive hands-on experience in a live, interactive 3D environment.
medtigo Points
medtigo points is our unique point redemption system created to award users for interacting on our site. These points can be redeemed for special discounts on the medtigo marketplace as well as towards the membership cost itself.
Community Forum post/reply = 5 points
*Redemption of points can occur only through the medtigo marketplace, courses, or simulation system. Money will not be credited to your bank account. 10 points = $1.
All Your Certificates in One Place
When you have your licenses, certificates and CMEs in one place, it's easier to track your career growth. You can easily share these with hospitals as well, using your medtigo app.
