Alport Syndrome

Updated: Jul 21, 2015
  • Author: Ramesh Saxena, MD, PhD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Overview

Practice Essentials

The term Alport syndrome encompasses a group of inherited, heterogeneous disorders involving the basement membranes of the kidney and frequently affecting the cochlea and eye as well. See the image below.

Electron micrograph of a kidney biopsy from a pati Electron micrograph of a kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).

The various forms of the disease include the following:

  • Autosomal recessive Alport syndrome (ARAS)
  • X-linked Alport syndrome (XLAS)
  • Autosomal dominant Alport syndrome (ADAS)

Signs and symptoms

Renal manifestations

  • Hematuria - Most common and earliest manifestation of Alport syndrome
  • Proteinuria - Develops in males with XLAS and in males and females with ARAS and ADAS
  • Hypertension - Usually present in males with XLAS and in males and females with ARAS and ADAS

Hypertension is usually detectable by the second decade of life. Edema and nephrotic syndrome are present in 30-40% of young adults with Alport syndrome; they are not common in early childhood, but their incidence progressively increases with age. With onset of renal insufficiency, symptoms of chronic anemia and osteodystrophy may become evident.

Hearing impairment

Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with Alport syndrome. About 50% of male patients with XLAS show sensorineural deafness by age 25 years, and about 90% are deaf by age 40 years.

Ocular manifestations

  • Anterior lenticonus - Occurs in approximately 25% of patients with XLAS; is the pathognomonic feature of Alport syndrome
  • Dot-and-fleck retinopathy - Most common ocular manifestation of patients with Alport syndrome, occurring in approximately 85% of males with XLAS
  • Posterior polymorphous corneal dystrophy - Rare in Alport syndrome
  • Temporal macular thinning - L1649R mutation in the COL4A5 gene occasionally causes severe temporal macular thinning, a prominent sign associated with XLAS

Leiomyomatosis

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome.

Autosomal dominant Alport syndrome

Renal manifestations and deafness in this rare form of Alport syndrome are usually identical to those occurring in patients with XLAS, but renal failure may occur at a later age.

See Clinical Presentation for more detail.

Diagnosis

See the list below:

  • Laboratory studies - Urinalysis reveals hematuria and proteinuria; hematologic studies demonstrate the extent of renal insufficiency
  • Biopsy - Tissue from the kidneys and skin should be examined for ultrastructural abnormalities; kidney biopsy most often provides the diagnosis if it is not established by skin biopsy
  • Genetic testing - If the diagnosis of Alport syndrome remains doubtful after skin or kidney biopsy, genetic analysis can be used to make a firm diagnosis and determine the condition’s mode of inheritance
  • Audiometry - All children with a history suggestive of Alport syndrome should undergo high-frequency audiometry to confirm the diagnosis, as well as periodic monitoring
  • Ophthalmic examination - This is important for the early detection and monitoring of anterior lenticonus, as well as perimacular flecks and other eye lesions
  • Renal ultrasonography - In the early stages of Alport syndrome, renal ultrasonograms show healthy-sized kidneys; with advancing renal failure, however, the kidneys shrink symmetrically and progressively and become echogenic

See Workup for more detail.

Management

Pharmacologic

Angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) should be administered to patients with Alport syndrome who have proteinuria with or without hypertension. Both classes of drugs apparently help to reduce proteinuria by decreasing intraglomerular pressure. Moreover, by inhibiting angiotensin II, a growth factor that is implicated in glomerular sclerosis, these drugs have a potential role in slowing sclerotic progression.

Treatment of bacterial infections, use of paricalcitol in adult patients with hyperparathyroidism, and use of statins in adult patients with dyslipoproteinemia might also help slow progression of Alport syndrome and reduce the incidence of cardiovascular events. Investigational therapies include stem cells, chaperone therapy, collagen receptor blockade, and anti-microRNA therapy. [1]

Surgical

Kidney transplantation is usually offered to patients with Alport syndrome who develop end-stage renal disease (ESRD). Recurrent disease does not occur in the transplanted kidney, and the allograft survival rate in these patients is similar to that in patients with other renal diseases. However, anti–glomerular basement membrane (anti-GBM) nephritis develops in a small percentage of transplant patients with Alport syndrome.

See Treatment and Medication for more detail.

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Background

The term Alport syndrome refers to a group of inherited, heterogeneous disorders involving the basement membranes of the kidney and frequently affecting the cochlea and eye as well. These disorders are the result of mutations in type IV collagen genes (see the image below). (See Pathophysiology and Etiology.)

Electron micrograph of a kidney biopsy from a pati Electron micrograph of a kidney biopsy from a patient with Alport syndrome. Note the splitting and lamellation of the glomerular basement membrane (see arrows).

The mode of inheritance is X-linked in 85% of cases, autosomal recessive in 10-15%, and autosomal dominant in a relatively small percentage of individuals with Alport syndrome. According to whether end-stage renal disease (ESRD) develops before or after age 30 years, X-linked Alport syndrome (XLAS) arbitrarily is categorized as either the juvenile type or the adult type. The juvenile type is encountered in 75% of kindreds. (See Pathophysiology and Etiology and DDx.)

Disease features

In 1927, Alport first described the combination of progressive hereditary nephritis with sensorineural deafness. The presence of the following features suggests the diagnosis of Alport syndrome (See DDx):

  • Presence of persistent glomerular hematuria
  • Family history of Alport syndrome or renal failure and no other obvious cause [2]
  • Progressive, high-frequency sensorineural deafness
  • Anterior lenticonus and perimacular flecks
  • Lack of alpha-3,4,5 collagen IV chains in glomerular basement membrane (GBM)

The diagnosis of Alport syndrome is confirmed by the presence of splitting or lamellation of the GBM on electron microscopy (see image below) or a pathogenetic mutation in the COL4A5 gene or 2 pathogenic mutations in COL4A3 or COL4A4 genes. [3]

Children with Alport syndrome may initially present with only persistent hematuria and a family history of hematuria. Auditory or ocular manifestations may appear later in life. The typical changes of the GBM are also age dependent and may be absent from initial biopsy samples obtained from young children with Alport syndrome. (See History, Physical Examination, and DDx.)

No specific treatment exists for patients with Alport syndrome, but those who develop ESRD are offered renal transplantation and usually have excellent allograft survival rates. (See Prognosis, Treatment, and Medication.)

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Pathophysiology and Etiology

The GBM is a sheetlike structure between the capillary endothelial cells and the visceral epithelial cells of the renal glomerulus. Type IV collagen is the major constituent of the GBM. Each type IV collagen molecule is composed of 3 subunits, called alpha (IV) chains, which are intertwined into a triple helical structure. Two molecules interact at the C-terminal end, and 4 molecules interact at the N-terminal end to form a "chicken wire" network. Six isomers of the alpha (IV) chains exist and are designated alpha-1 (IV) to alpha-6 (IV). The genes coding for the 6 alpha (IV) chains are distributed in pairs on 3 chromosomes (see Table 1, below), as follows [4] :

  • The alpha-1 (IV) and alpha-2 (IV) chains are encoded by genes COL4A1 and COL4A2, respectively, and are located on chromosome 13
  • The alpha-3 (IV) and alpha-4 (IV) chains are encoded by a similar pair of genes (ie, COL4A3 and COL4A4, respectively) and are located on chromosome 2 [5]
  • The alpha-5 (IV) and alpha-6 (IV) chains are encoded by genes COL4A5 and COL4A6, respectively, on the X chromosome

Table 1. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in Alport Syndrome (Open Table in a new window)

Alpha (IV) Chain Genes Chromosomal Location Mutation
Alpha-1 (IV) COL4A1 13 Unknown
Alpha-2 (IV) COL4A2 13 Unknown
Alpha-3 (IV) COL4A3 2 ARASa
Alpha-4 (IV) COL4A4 2 ARAS
Alpha-5 (IV) COL4A5 X XLASb
Alpha-6 (IV) COL4A6 X Leiomyomatosisc
a Autosomal recessive Alport syndrome (mutations spanning 5' regions of COL4A5 and COL4A6 genes).



b X-linked Alport syndrome.



c Autosomal recessive Alport syndrome.



Distribution

The alpha-1 (IV) and alpha-2 (IV) chains are ubiquitous in all basement membranes (see Table 2, below), while the other type IV collagen chains have more restricted tissue distribution. The basement membranes of the glomerulus, cochlea, lung, lens capsule, and Bruch and Descemet membranes in the eye contain alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains, in addition to alpha-1 (IV) and alpha-2 (IV) chains. The alpha-6 (IV) chains are present in epidermal basement membranes.

Table 2. Tissue Distribution of Alpha (IV) Chains (Open Table in a new window)

Alpha (IV) Chain Tissue Distribution
Alpha-1 (IV) Ubiquitous
Alpha-2 (IV) Ubiquitous
Alpha-3 (IV) GBM, distal TBMa, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-4 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-5 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea
Alpha-6 (IV) Distal TBM, epidermal basement membrane
a Tubular basement membrane.

Mutations

Alport syndrome, which is genetically heterogeneous, is caused by defects in the genes encoding alpha-3, alpha-4, or alpha-5 chains of type IV collagen of the basement membranes. The estimated gene frequency ratio of Alport syndrome is 1:5000. The following 3 genetic forms of Alport syndrome exist:

  • XLAS - Results from mutations in the COL4A5 gene; accounts for 85% of cases of Alport syndrome
  • Autosomal recessive Alport syndrome (ARAS) - Caused by mutations in either the COL4A3 or COL4A4 gene; responsible for approximately 10-15% of cases
  • Autosomal dominant Alport syndrome (ADAS) - Rare; caused by mutations in either the COL4A3 or COL4A4 gene in at least some families and accounts for the remainder of cases (see Table 1)

More than 300 mutations have been reported In the COL4A5 genes from families with XLAS. Most COL4A5 mutations are small; these include missense mutations, splice-site mutations, and deletions of less than 10 base pairs.

Approximately 20% of the mutations are major rearrangements at the COL4A5 locus (ie, large- and medium-sized deletions). A particular type of deletion spanning the 5' ends of the COL4A5 and COL4A6 genes is associated with a rare combination of XLAS and diffuse leiomyomatosis of the esophagus, tracheobronchial tree, and female genital tract.

In patients with Alport syndrome, no mutations have been identified solely in the COL4A6 gene. To date, only 6 mutations in the COL4A3 gene and 12 mutations in the COL4A4 gene have been identified in patients with ARAS. Patients are either homozygous or compound heterozygous for their mutations, and their parents are asymptomatic carriers. The mutations include amino acid substitutions, frameshift deletions, missense mutations, in-frame deletions, and splicing mutations. ADAS is rarer than XLAS or ARAS. Recently, a splice site mutation resulting in skipping of exon 21 in the COL4A3 gene was found in ADAS.

Mutation-induced GBM changes

The primary abnormality in patients with Alport syndrome—resulting in aberration of basement membrane—lies in the noncollagenous (NC1) domain of the C-terminal of the alpha-5 (IV) chain in XLAS and that of alpha-3 (IV) or alpha-4 (IV) chains in ARAS and ADAS.

In the early developmental period of the kidney, alpha-1 (IV) and alpha-2 (IV) chains predominate in the GBM. With glomerular maturation, alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains become preponderant through a process called isotype switching. Evidence shows that alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains combine to form a unique collagen network. Abnormality of any of these chains, as observed in patients with Alport syndrome, limits formation of the collagen network and prevents incorporation of the other collagen chains.

Evidence has demonstrated that isoform switching of type IV collagen becomes developmentally arrested in patients with XLAS. This leads to retention of the fetal distribution of alpha-1 (IV) and alpha-2 (IV) isoforms and the absence of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) isoforms. The cysteine-rich alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains are thought to enhance the resistance of GBM to proteolytic degradation at the site of glomerular filtration; thus, anomalous persistence of alpha-1 (IV) and alpha-2 (IV) isoforms confers an unexpected increase in the susceptibility of GBM to proteolytic enzymes, leading to basement membrane splitting and damage.

How defective collagen chains result in glomerulosclerosis remains unclear. Evidence now suggests that accumulation of type V and VI collagen chains (along with alpha-1 [IV] and alpha-2 [IV] chains) in the GBM occurs as a compensatory response to the loss of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains. These proteins spread from a normal subendothelial location and occupy the full width of GBM, altering glomerular homeostasis and resulting in GBM thickening and impairment of macromolecular permselectivity, with subsequent glomerular sclerosis, interstitial fibrosis, and renal failure.

Experimental studies implicate transforming growth factor beta (TGF-beta) and matrix metalloproteinases in the progression of renal disease in Alport syndrome. Further studies are needed to define their precise pathogenetic role and their potential relevance as therapeutic targets.

Hematologic disorders

Several reports describe families with hereditary nephritis associated with deafness, megathrombocytopenia (giant platelets), and, in some families, granulocyte abnormalities. Clinical features include bleeding tendency, macrothrombocytopenia, abnormalities of platelet aggregation (ie, Epstein-Barr syndrome), and, occasionally, neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechtner syndrome).

In most patients, the autosomal dominant pattern of inheritance is observed. In only 2 reports, focal thickening, splitting, or lamellation of the GBM was identified. The basement membrane of these patients showed normal expression of a chain of type IV collagen. So far, the genetic loci involved remain unknown.

Leiomyomatosis

All patients with Alport syndrome diffuse leiomyomatosis complex have been found to have deletions that span the 5' ends of the COL4A5 and COL4A6 genes.

Anti-GBM nephritis

The cause of anti-GBM nephritis is unclear, but about 3-5% of males with Alport syndrome who undergo renal transplantation develop this disorder. These individuals usually have early onset Alport syndrome with clinically significant hearing loss and ESRD by about age 20 years.

Patients who develop anti-GBM nephritis possess circulating anti-GBM antibodies. In persons with ARAS, antibodies predominantly bind to the alpha-3 (IV) and alpha-4 (IV) collagen chains, whereas most antibodies in patients with XLAS bind to the alpha-5 (IV) chain. [5, 6, 7] The antigens recognized by the anti-GBM antibodies are not expressed in the native kidneys of patients with Alport syndrome but are present in the transplanted kidneys.

Recent studies suggest that alpha-5 (IV) collagen forms distinct alpha-345 (IV) and alpha-1256 (IV) networks in the GBM. It has been observed that in patients with posttransplantation anti-GBM nephritis, quaternary epitopes within alpha-345NC1 hexamers may initiate an alloimmune response after transplantation, triggering the formation of anti-GBM antibodies. Reliable detection of alloantibodies by immunoassays using alpha-345NC1 hexamers may facilitate early and accurate diagnosis and improve outcomes. [5]

At present, the only way to determine whether a patient with Alport syndrome will develop posttransplant anti-GBM nephritis is to perform the transplant. Certain patients, however, are at very low risk for developing posttransplant anti-GBM nephritis, including those with normal hearing, patients with late progression to ESRD, and females with XLAS.

Posttransplant anti-GBM nephritis usually develops within the first year of the transplant surgery. Patients typically develop rapidly progressive glomerulonephritis with findings on kidney biopsy showing crescentic glomerulonephritis and linear immune deposits along the GBM. Unlike de novo anti-GBM nephritis, pulmonary hemorrhage is never observed in posttransplant anti-GBM nephritis in patients with Alport syndrome, because the patient's lung tissue does not contain the Goodpasture antigen (NC1 component of the alpha-3 [IV] chain). Treatment with plasmapheresis and cyclophosphamide is usually unsuccessful, and most patients lose the allograft. [8] However, a case of successful treatment with plasmapheresis and intravenous immunoglobulin has recently been reported. [9]

Retransplantation in most patients results in recurrence of anti-GBM nephritis despite the absence of detectable circulating anti-GBM antibodies before transplantation.

Because of excellent graft survival rates and a very low incidence of clinical anti-GBM disease, renal transplantation is not contraindicated in patients with Alport syndrome. However, in patients who have already lost an allograft due to posttransplant anti-GBM nephritis, the optimal management is uncertain because of the high likelihood of recurrence and subsequent allograft loss.

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Epidemiology

Occurrence in the United States and internationally

A rare disease, Alport syndrome accounts for approximately 3% of children and 0.2% of adults with ESRD in the United States. [10] In Europe, Alport syndrome accounts for 0.6% of patients with ESRD.

Sex- and age-related demographics

The common X-linked form of Alport syndrome leading to ESRD predominantly affects male individuals.

Hematuria is usually discovered during the first years of life in males with Alport syndrome. If individuals do not have hematuria during the first decade of life, they are unlikely to have Alport syndrome.

Proteinuria is usually absent in childhood, but this condition eventually develops in males with XLAS and in males and females with ARAS.

Hearing loss and ocular abnormalities are never present at birth; they usually become apparent by late childhood or early adolescence, generally before the onset of renal failure.

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Prognosis

Progression of renal failure

Renal prognosis in Alport syndrome depends on the kind of mutation causing the condition. The probability of ESRD in people younger than 30 years is significantly higher (90%) in patients with a large rearrangement of the COL4A5 gene than it is in those with minor mutations (50-70%). Furthermore, the rate of progression of renal disease is fairly constant among patients within a particular family but shows significant variability between different families.

XLAS

ESRD develops in virtually all males with XLAS, with the degree of proteinuria in the patient being predictive of the rate of disease progression. Male patients with the typical X-linked disease have a renal half-life of about 25 years, with about 90% of these individuals developing ESRD by age 40 years. [11]

Patients with a family history of juvenile-type Alport syndrome or with early onset deafness and ocular changes typically progress to ESRD by age 20-30 years.

Female patients with XLAS tend to have mild renal disease, with many surviving to old age. However, studies have shown significant renal morbidity in female patients who develop proteinuria and hearing loss. [12, 13] The reported probability of ESRD in female patients is 12% by age 40 years, 30% by age 60 years, and 40% by age 80 years.

Risk factors for progression to ESRD are episodes of gross hematuria in childhood, nephrotic range proteinuria, and diffuse GBM thickening on examination with an electron microscope.

ARAS

The renal prognosis for all patients, male and female, with autosomal recessive disease is poor, with most progressing to ESRD.

ESRD

In a study of 58,422 patients commencing renal replacement therapy for ESRD, including 296 patients with Alport syndrome, dialysis and renal transplant outcomes were comparable in Alport and non-Alport patients treated during the more recent part of the 45-year study period (1996-2010). In the earlier study period (1965-1995), patients with Alport syndrome had significantly better outcomes. [14]

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Patient Education

Provide pre-ESRD education for patients with Alport syndrome to discuss various options and issues regarding renal replacement therapy (eg, dialysis, transplantation). Arrange dietary counseling for patients approaching ESRD.

Avoid administering nephrotoxins in patients with Alport syndrome, including over-the-counter nonsteroidal analgesic agents.

In asymptomatic patients, stress the importance of yearly physical examinations and laboratory evaluations. Advise patients to receive audiometry and visual testing every 2 years.

Advise parents affected with Alport syndrome and potential carriers of the disorder to obtain genetic counseling.

For patient education information, see Urine and blood Analsis.

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