Alport Syndrome

Article Author:
Simon Watson
Article Author:
Sandeep Padala
Article Editor:
Jeffrey Bush
Updated:
3/24/2020 10:23:15 PM
PubMed Link:
Alport Syndrome

Introduction

Alport syndrome, also known as hereditary nephritis is a genetic disorder arising from the mutations in the genes encoding alpha-3, alpha-4, and alpha-5 of type IV collagen (COL4A3, COL4A4, COL4A5) or collagen IV α345 network.[1]

The type IV collagen alpha chains are primarily located in the kidneys, eyes, and cochlea. Alport's syndrome is X-linked (XLAS) and can be transmitted in an autosomal recessive (ARAS) or autosomal dominant fashion(ADAS). In 1927, the syndrome of hereditary nephritis and deafness was described by a British physician, A. Cecil Alport. It was observed that hematuria was the most common symptom and males were affected more than the females. In 1961, it was named Alport syndrome after described in multiple family members.[2][3][4] It is characterized by renal failure, bilateral sensorineural hearing loss, and eye abnormalities. Eventually, the patients present with proteinuria, hypertension, progressive loss of kidney function (gradual decline in GFR) and end-stage renal disease (ESRD).[5]

Etiology

In 80% of cases, Alport syndrome is inherited in an X-linked pattern and caused by COL4A5 gene mutations, although other inheritance patterns do exist. It can be inherited as an autosomal recessive or dominant pattern by mutations in COL4A3 or COL4A4 gene. Approximately 80% of men with the XLAS develop some degree of hearing loss till they reach teenage.[6]

Epidemiology

Alport syndrome affects about 1 in 50,000 newborns and males are more likely to be symptomatic than females. It is estimated that approximately 30,000 to 60,000 people in the United States (US) have the disorder. In the US, the overall incidence of end-stage renal disease (ESRD) in children is about 3% and 0.2% in the adult population.[7]

Pathophysiology

The pathophysiology of Alport syndrome is impaired production and deposition of collagen IV α345 network in the basement membranes of the glomerulus, cochlea (inner ear) and eye. ARAS transmission is due to mutations in both the alleles of COL4A3 and COL4A4, whereas ADAS is caused by heterozygous mutations. With the use of next-generation sequencing (NGS), it has shown that ADAS accounts for a greater number of cases. Compared to XLAS, patients with ADAS have a slower rate of progression to ESRD and less likely to have extra-renal manifestations. [8][9] The glomerular basement membrane (GBM) in Alport syndrome is more prone to proteolytic injury leading to activation of adhesion kinase in podocytes, endothelin receptors, glomerular inflammation, and tubulointerstitial fibrosis and ESRD.[10][11][12][13]

Histopathology

Initially, kidney biopsy specimens examined through light microscopy may be normal. As the disease progresses non-specific findings may appear. These include focal and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and presence of lymphocytes and plasma cells. Immunofluorescence studies yield negative results. Electron microscopy of the kidney reveals longitudinal splitting of the GBM lamina densa.

As the alpha-5 chain of type IV collagen is also expressed in the epidermis, a skin biopsy can be used to establish a diagnosis. Immunofluorescence studies on skin biopsy specimens are often diagnostic. Patients with XLAS may also display abnormalities of alpha-2 collagen expression in the skin.[14][15]

History and Physical

A thorough history and physical examination must be obtained along with family history. Laboratory evaluation should include urinalysis (UA), urine microscopy, and renal function panel. Individuals with Alport syndrome may develop symptoms of hematuria, proteinuria, edema, hypertension, and progressive decline in renal functions and eventual ESRD. Over time, the symptoms worsen, and the patients experience worsening proteinuria, hypertension, a decline in GFR, and development of ESRD. Time to ESRD is around 16 to 35 years of age. They can also present with gross hematuria following an upper respiratory tract infection.[16] During late childhood, people with Alport's syndrome frequently develop bilateral sensorineural hearing loss caused by abnormalities of type IV collagen in the inner ear.[17] Hearing loss becomes apparent in late childhood or early adolescence, usually before the onset of kidney failure, and starts with high-frequency loss. 

Multiple ocular findings can be seen in patients with Alport syndrome. Affected individuals may have a cone-shaped lens (anterior lenticonus), leading to abnormal refraction and a decreased visual acuity. Other abnormalities include subcapsular cataracts, abnormal pigmentary changes in the retina with yellow or white flecks (dot-and-fleck retinopathy), posterior polymorphous dystrophy and corneal erosions. [18][19][20][21]  

Evaluation

Patients typically present with persistent microscopic hematuria before the age of 10 years. This is due to the defective GBM permitting the passage of red blood cells.[22] The clinical suspicion for Alport syndrome should be high in a patient with hematuria, proteinuria, abnormal renal indices along with ear and eye manifestations. UA would reveal blood and protein, and urine microscopy should be performed to evaluate for acanthocytes. Renal biopsy is indicated in the setting of abnormal UA, presence of acanthocytes or red blood cell casts or abnormal renal indices. Any patient with suspected Alport syndrome should be referred to otorhinolaryngology for high-frequency hearing loss and ophthalmology for the eye examination. Due to the defective collagen, the lens lacks the integrity to maintain the normal shape leading to anterior lenticonus into the anterior chamber.[23][24][23]

Genetic testing can help establish the diagnosis and determine the inheritance pattern of an individual and their family members. Molecular Genetic testing is non-invasive, accurate, and gives the prognosis as the underlying mutation can be revealed. Next-generation sequencing (NGS) analyses of COL4A3, COL4A4, COL4A5 is recommended in patients with no family history of Alport's syndrome.[8][25]. For patients with positive family history, testing of the target gene is recommended. If the genetic defect does not match the family genetic mutation, a renal biopsy is preferred. In males with XLAS, the GBM splitting increases from approximately 30 percent to more than 90 percent by the age of 30 years.[26] 

Patients without the characteristic GBM splitting can be identified by immunostaining the type IV collagen of the alpha-3, alpha-4, and alpha-5 chains of the GBM. A less invasive procedure, a skin biopsy can be performed in a child with suspected XLAS using a monoclonal antibody against the alpha-5 of the type IV collagen chain.

Treatment / Management

Unfortunately, there is no specific treatment for Alport syndrome. Treatment is focused on limiting the progression of proteinuria and kidney disease. Options include angiotensin-converting enzyme inhibitors (ACEi), Angiotensin receptor blockers (ARBs) for the management of proteinuria, hypertension, and CKD management. Depending upon the degree of proteinuria, diuretics can be used. Although the treatment may delay the onset of renal impairment, most people affected by Alport's will ultimately require dialysis or a kidney transplant.[27][28][29] 

ARB- delays the progression of CKD or ESRD by reducing the intra-glomerular pressure and proteinuria. Despite normal renal functions, initiating therapy with ARB's has been shown to have a significant impact on the development of ESRD[30]

The use of cyclosporine has not shown any benefit and is not recommended. For the patients with ocular involvement, specifically anterior lenticonus, clear lens phacoemulsification with intraocular lens implantation can be considered. For patients with concomitant hearing loss, hearing aids are usually very effective. The hearing loss is not impacted by kidney transplantation. As with any hereditary disease, psychosocial support for all of the affected family members is important.[31]

Patients with Alport syndrome have no contraindication for renal transplantation. There is no recurrence of the primary disease, as the transplanted kidney would have normal GBM. Antibodies against COL4A5 is found in males with XLAS, but very few patients also have antibodies against COL4A3.[32][33][34][35].

Post renal transplantation, there is a 3% risk of de novo anti-GBM antibody disease or Alport posttransplant nephritis in XLAS with COL4A3. Generally, it relapses in the first year of transplantation.[19][36][37] 

The affected patients typically have circulating anti-GBM antibodies leading to crescentic glomerulonephritis and graft loss.[38][39] Patients with ADAS do not appear to be at increased risk for de novo anti-GBM disease following kidney transplantation. The treatment of post-transplant anti-GBM disease involves plasmapheresis along with cyclophosphamide and methylprednisolone with minimal benefit. Retransplantation in these patients has a high risk of recurrence.

Differential Diagnosis

The differential diagnosis includes:

  • Immunoglobulin A nephropathy

  • Thin GBM disease

  • Acute post-streptococcal glomerulonephritis

  • Medullary cystic disease

  • Multicystic renal dysplasia

  • Polycystic kidney disease

The most important diagnostic consideration in patients with Alport syndrome is thin basement membrane (TBM) disease, which is a collagen IV related nephropathy closely related to Alport syndrome. In many individuals with the disorder, the same genes appear to be involved. Unlike those with Alport syndrome, few extra-renal findings are present, and symptoms are less severe, with progression to renal impairment rarely found. Differentiating these disease processes is a challenge, particularly in younger or female patients who are less likely to have other associated symptoms.[40]

Prognosis

In the X-linked disease form, the most common type of Alport syndrome, about 50% of males require dialysis or kidney transplantation by age of 30 years, and approximately 90% develop ESRD before 40. Female patients with X-linked Alport syndrome have a better prognosis with about 12% developing the end-stage renal disease (ESRD) by age 40. By age 60, this rate increases to about 30% and by 60 years of age, the rate of ESRD approaches 40%. In the female population, proteinuria and hearing loss are found to be risk factors for the progression to ESRD. In comparison, the autosomal recessive form of Alport syndrome can cause kidney failure by age 20 while the autosomal dominant form of the disease typically has a delay in ESRD until middle age.[41]

Complications

Alport syndrome affects multiple organ systems. It can lead to the following complications:

  • ESRD
  • Hearing loss
  • Visual defects
  • Leiomyomatosis (smooth muscle overgrowth in the respiratory and gastrointestinal tract)
  • Aneurysms of the thoracic and abdominal aorta
  • Mental retardation

Consultations

Alport syndrome is managed through a multidisciplinary approach as multiple organ systems are involved. An internist, intensivist, nephrologist, otorhinolaryngologist, ophthalmologist, and a geneticist are involved in the treatment and management of Alport syndrome.

Enhancing Healthcare Team Outcomes

Alport syndrome is a genetic disorder that affects multiple organs. The disorder is best managed by an interprofessional team that includes a geneticist, nephrologist, ophthalmologist, ENT surgeon, and an internist/pediatrician. In most cases, the disorder presents in the first decade of life. Once the diagnosis is made, the workup of siblings and other members of the family is recommended. Within the first three decades of life, the majority of Alport syndrome patients develop ESRF and a need for dialysis.


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