Alport Syndrome

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 Pathophysiology and Etiology.)

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, Cecil 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 kidney failure and no other obvious cause ^[5]
• Progressive, high-frequency sensorineural deafness
• Anterior lenticonus and perimacular flecks
• Lack of alpha-3,4,5 collagen IV chains in glomerular basement membrane (GBM)

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 Presentation and DDx.)

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

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[6] :

• 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[7]

• 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)

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)

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 kidney failure.

Experimental studies implicate transforming growth factor beta (TGF-beta) and matrix metalloproteinases in the progression of kidney 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 the following:

• Bleeding tendency
• Macrothrombocytopenia
• Abnormalities of platelet aggregation (ie, Epstein-Barr syndrome)
• 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 kidney 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.[7, 8, 9] 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.

Some 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.[7]

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.[10] However, a case of successful treatment with plasmapheresis and intravenous immunoglobulin has been reported.[11]

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, kidney 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.

A rare disease, Alport syndrome accounts for approximately 2.2% of children and 0.2% of adults with ESRD in the United States.[12] In Europe, Alport syndrome accounts for 0.6% of patients with ESRD.

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

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 eventually develops in males with XLAS and in both 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.

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 kidney disease is fairly constant among patients within a particular family but shows significant variability among 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 kidney half-life of about 25 years, with about 90% of these individuals developing ESRD by age 40 years.[13]

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 kidney disease, with many surviving to old age. However, studies have shown significant renal morbidity in female patients who develop proteinuria and hearing loss.[14, 15] 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. 

A systematic review of 26 studies including 148 patients with ARAS found that 62% of patients developed ESRD, at median age of 21 years and 64% had sensorineural hearing loss by a median age of 13 years. Ocular abnormality was reported in 17% of patients; median age of onset, reported in only two patients, was 32 years. There was genotype-phenotype correlation according to the number of missense mutations. Patients with missense mutations had delayed onset of hematuria, ESRD, and sensorineural hearing loss and a lower prevalence of extrarenal manifestations. Patients without missense mutations tended to be from consanguinous families and had more grave outcomes at earlier age.[16]

ESRD

In a study of 58,422 patients commencing renal replacement therapy for ESRD, including 296 patients with Alport syndrome, dialysis and kidney 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.[17]

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 undergo 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 Blood in the Urine (Hematuria). See also the National Institute of Health's Genetic and Rare Diseases Information Center page on Alport Syndrome.

In any child or adolescent with persistent microscopic hematuria, carefully seek a family history of hematuria, early onset deafness, and kidney insufficiency (especially in male patients).[5]

In patients with typical clinical findings for Alport syndrome but a negative family history for the disease, suspect the autosomal recessive form. Occasionally, mild clinical manifestations are observed in carriers (heterozygotes) of autosomal recessive Alport syndrome (ARAS).

Renal manifestations

Hematuria

Gross or microscopic hematuria is the most common and earliest manifestation of Alport syndrome. Microscopic hematuria is observed in all males and in 95% of females. This condition is usually persistent in males, whereas it can be intermittent in females. Like immunoglobulin A (IgA) nephropathy, approximately 60-70% of patients experience episodes of gross hematuria, often precipitated by upper respiratory infection, during the first 2 decades of life. Hematuria is usually discovered during the first years of life in males. If a male patient does not present with hematuria during the first decade of life, he is unlikely to have Alport syndrome.

Proteinuria

Proteinuria is usually absent in childhood but eventually develops in males with X-linked Alport syndrome (XLAS) and in males and females with ARAS. Proteinuria usually progresses with age and can occur in the nephrotic range in as many as 30% of patients. Significant proteinuria is infrequent in females with XLAS, but it may occur.

Hypertension

This condition is usually present in males with XLAS and in males and females with ARAS. Incidence and severity increases with age and degree of kidney failure.

Hearing impairment

Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with Alport syndrome. Some families with Alport syndrome have severe nephropathy but normal hearing. Hearing loss is never present at birth. Bilateral, high-frequency sensorineural hearing loss usually begins by late childhood or early adolescence, generally before the onset of kidney failure. In the early stages of the disease, hearing loss is detectable only by means of audiometry.

As hearing loss progresses, it extends to the low frequencies, including those of human conversation, and patients require hearing aids. Hearing impairment is always associated with renal involvement.

About 50% of male patients with X-linked Alport syndrome show sensorineural deafness by age 25 years, and about 90% are deaf by age 40 years.

Ocular manifestations

Anterior lenticonus

Anterior lenticonus, which occurs in approximately 25% of patients with XLAS, is the pathognomonic feature of Alport syndrome. In this condition, the lens surface protrudes conically into the anterior chamber of the eye because of a thin and fragile basement membrane of the lens capsule. The lenticonus is most marked anteriorly because the capsule is thinnest there, the stresses of accommodation are more marked, and the lens is least supported.

Anterior lenticonus is not present at birth but is manifested by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently. The condition is not accompanied by eye pain, redness, or night blindness, and no defect in color vision occurs.

Dot-and-fleck retinopathy

This is the most common ocular manifestation of patients with Alport syndrome, occurring in approximately 85% of males with XLAS. Rarely observed in childhood, it usually becomes apparent at the onset of kidney failure. Dot-and-fleck retinopathy is usually asymptomatic, with no associated visual impairment or night blindness.

Posterior polymorphous corneal dystrophy

This condition is rare in Alport syndrome. Most patients are asymptomatic, although some of them may develop slowly progressive visual impairment.

Temporal macular thinning

The L1649R mutation in the COL4A5 gene occasionally causes severe temporal macular thinning, a prominent sign associated with XLAS.[18]

Leiomyomatosis

Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography (CT) scanning or magnetic resonance imaging (MRI).

ARAS

ARAS is much less common than XLAS, accounting for 10-15% of all patients with Alport syndrome. ARAS is usually observed in consanguineous families. The parents are asymptomatic or mildly affected, while their children (ie, both boys and girls) are often equally and severely affected. The clinical features are usually identical to those observed in patients with XLAS. Kidney failure may have an earlier onset. Dot-and-fleck retinopathy and anterior lenticonus also occur in patients with ARAS.

ADAS

This rare form of Alport syndrome is present in successive generations, and males and females are often equally and severely affected. Renal manifestations and deafness are usually identical to those occurring in patients with XLAS, but kidney failure may occur at a later age. Clinical features confined to autosomal dominant Alport syndrome (ADAS) include the following:

• Bleeding tendency
• Macrothrombocytopenia
• Abnormalities of platelet aggregation (Epstein syndrome)
• Neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechtner syndrome) - Occur only occasionally

The findings on physical examination may initially be unremarkable, but with time, patients develop progressive kidney failure manifested by hypertension, edema, and anemia. Moreover, various extrarenal features may also be observed.

Renal manifestations

Clinical renal findings include the following:

• 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 kidney insufficiency, symptoms of chronic anemia and osteodystrophy may become evident

Hearing impairment

In the early stages, hearing impairment is detectable only by audiometry, with bilateral hearing loss of high tones in frequencies ranging from 2000-8000 hertz (Hz).

In males with XLAS and in males and females with ARAS, the hearing deficit is progressive and eventually involves lower frequencies, including those of conversational speech.

In females with XLAS, hearing loss occurs less frequently and later in life than it does in males. The risk of developing hearing loss by age 40 years is approximately 90% in males and 10% in females with XLAS. Approximately 60% of patients with ARAS usually develop hearing loss when they are younger than 20 years. In patients with Alport syndrome, studies of brainstem auditory-evoked responses indicate the cochlea as the site of the lesion involved with hearing impairment.

Animal studies reveal marked thickening of the basement membranes of the strial vessels of the cochlea; however, only limited information is available regarding the inner ear histology in humans with Alport syndrome. Striking alterations of the stria vascularis of the cochlea are described.

Ocular manifestations

Anterior lenticonus

As previously mentioned, anterior lenticonus is the pathognomonic feature of patients with Alport syndrome, and its presence in any individual is highly suggestive of the disease. This ocular condition serves as a valuable marker of severity in Alport syndrome and is almost invariably accompanied by progressive kidney failure and hearing loss. (Patients with Alport syndrome and anterior lenticonus usually progress to end-stage renal disease (ESRD) and deafness before age 30 years.)

Diagnosis of anterior lenticonus is made by slit lamp examination. Minor degrees of lenticonus are difficult to detect but are suggested by distinctive oil droplet appearance on the red reflex on slit lamp examination.

The diagnosis is confirmed when the central part of the lens projects anteriorly 3-4 mm in an axial projection on biomicroscopic examination. The condition is usually bilateral, causes a slowly progressive axial myopia, and (rarely) may progress to anterior capsular cataract, for which surgical extraction is required.

Ultrastructure analysis of the anterior lens capsule by electron microscopy confirms the diagnosis of Alport syndrome.[19] This condition rarely progresses to spontaneous rupture of the lens capsule, and posterior lenticonus is very uncommon.

Dot-and-fleck retinopathy

This condition is the most common ocular manifestation in patients with Alport syndrome, occurring in approximately 85% of males with XLAS. Dot-and-fleck retinopathy is rarely observed in childhood, instead usually becoming apparent at the onset of kidney failure.

Numerous bilateral, white and yellow perimacular dots and flecks occur in this condition. These spare the fovea but can spread to the periphery. No associated visual impairment or night blindness occurs. Typically, dot-and-fleck retinopathy does not fluoresce with angiography.

These dots are thought to be located at the level of the retinal pigment epithelium–Bruch membrane–choriocapillaris complex. The abnormal basement membrane proteins in patients with Alport syndrome may result in enhanced permeability of the Bruch membrane and the underlying choriocapillaris, allowing accumulation of lipofuscin and other undefined substances in the retinal pigment epithelium or in the Bruch membrane.

Posterior polymorphous corneal dystrophy

A rare ocular sign of Alport syndrome, posterior polymorphous corneal dystrophy manifests as clear vesicles alone or in groups (string of pearls) on the endothelial surface of the cornea. This condition is usually bilateral but can be unilateral or asymmetrical. It is attributed to the lamellation and thickening of the outer layer of the Descemet membrane. The occurrence of posterior polymorphous corneal dystrophy in any individual is highly suggestive of Alport syndrome.

Macular holes

Giant macular holes have been associated with Alport syndrome. A case of bilateral full-thickness macular holes measuring > 1500 µm at their smallest diameters has been reported. The very large dimensions of both macular holes were indicative of a bad prognosis regarding hole closure.[20]

Leiomyomatosis

An association of Alport syndrome with diffuse leiomyomatosis of the esophagus and tracheobronchial tree is reported in at least 26 families. These patients have typical X-linked Alport syndrome, usually the juvenile type, with a high incidence of bilateral posterior subcapsular cataracts. Female patients have vulvar and clitoral leiomyomatosis and other findings like those of male patients. Symptoms appear in late childhood and include dysphagia, postprandial vomiting, recurrent bronchitis, dyspnea, cough, and stridor.

Laboratory studies

In individuals with Alport syndrome, urinalysis reveals microscopic or gross hematuria. Proteinuria is found in male patients with X-linked Alport syndrome (XLAS) and in patients of both sexes with autosomal recessive disease. Hematologic studies demonstrate the extent of kidney insufficiency.

Biopsy

Tissue from the kidneys and skin should be examined for ultrastructural abnormalities. Skin biopsy is less invasive than kidney biopsy and should be performed first. Kidney biopsy most often provides the diagnosis if skin biopsy does not establish it.

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 (ie, high-frequency sensorineural hearing loss), as well as periodic monitoring.

Ophthalmic evaluation

Ophthalmic examination 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, ultrasonograms show healthy-sized kidneys; with advancing kidney failure, however, the kidneys shrink symmetrically and progressively and become echogenic.

Urinalysis

A urinary dipstick test and a 24-hour urine specimen for protein and creatinine should be performed to detect hematuria and proteinuria. Also, urinary sediment should be analyzed by microscope to detect dysmorphic red blood cells and red blood cell casts.

Whenever possible, the first-degree relatives of a patient with Alport syndrome should also be screened for microscopic hematuria of glomerular origin.

Proteinuria is usually absent in the first few years of life but eventually develops in male patients with X-linked Alport syndrome (XLAS) and in people of both sexes with autosomal recessive disease. The degree of proteinuria usually increases with age and may reach the nephrotic range in 30-40% of young adults with Alport syndrome.

Blood analysis

Blood counts and serum electrolyte, blood urea nitrogen (BUN), and creatinine levels reflect the degree of renal insufficiency in Alport syndrome. In addition, individuals with nephrotic syndrome may have clinically significant hypoalbuminemia and hypercholesterolemia.

Some patients with the autosomal dominant form of Alport syndrome also have thrombocytopenia, giant platelets, and granulocytic inclusions.

Kidney biopsy

Percutaneous kidney biopsy is an important part of the diagnostic workup. The test should be performed at a medical center equipped for ultrastructural analysis with electron microscopy. A medical center that has facilities for evaluating collagen chains of the basement membrane by means of immunohistochemistry is also desirable but not required.

Biopsy may be deferred in a patient with a strong family history of biopsy-proven Alport disease who presents with characteristic clinical features.

Skin biopsy

Because the alpha-5 (IV) chain of type IV collagen is also expressed in the epidermis, immunofluorescent examination of a skin biopsy specimen can be used to establish the diagnosis. Approximately 80% of male patients and 60% of female patients with XLAS have no alpha-5 (IV) collagen in the epidermal basement membrane, with the interruption of alpha-5 (IV) expression being total in males and segmental in females.

Studies have shown that many individuals with X-linked Alport syndrome also display abnormalities of alpha-2 (IV) collagen expression in the skin.[21] In addition, most individuals with autosomal recessive Alport syndrome do not express alpha-3 (IV), alpha-4 (IV), or alpha-5 (IV) collagens in skin. Healthy individuals and patients with thin-membrane disease have normal expression of alpha-5(IV) in the skin.

Skin biopsy is especially useful if a kidney biopsy poses an excessive risk, such as in patients with end-stage renal disease (ESRD).

The absence of alpha-5 (IV) collagen chains in the epidermal basement membrane on skin biopsy is diagnostic of XLAS. In such cases, kidney biopsy is not necessary for diagnosis; however, the absence of alpha-5 (IV) chains in the epidermal basement membrane is observed in only 80% of males with XLAS. Therefore, the presence of alpha-5 (IV) chains in the epidermal basement membrane does not rule out the diagnosis of XLAS; moreover, the alpha-5 (IV) chain is expressed in the epidermal basement membrane in autosomal recessive disease. This indicates that a mutation in the alpha-5 (IV) chain permits its expression in skin but not in the kidney in XLAS and autosomal recessive Alport syndrome (ARAS).

Light microscopy

In early Alport syndrome, light microscopy findings for kidney biopsy specimens may be normal. The findings that occur with disease progression are nonspecific, contributing little toward the diagnosis. They include segmental and focal glomerulosclerosis, tubular atrophy, interstitial fibrosis, and infiltration by lymphocytes and plasma cells with clusters of foam cells of uncertain origin. Findings on standard immunofluorescence studies are usually negative.

Monoclonal antibodies

Monoclonal antibodies directed against alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen can be used to evaluate the glomerular basement membrane (GBM) for the presence or absence of these chains. Their absence is diagnostic of Alport syndrome and has not been described in any other condition.

In addition, expression of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains in the kidney can differentiate XLAS and ARAS. In most patients with XLAS, these chains are absent from the GBM and distal TBM. On the other hand, in ARAS, no expression of alpha-3 (IV) and alpha-4 (IV) chains exists, while the alpha-5 (IV) chain is expressed in the GBM and distal tubular basement membrane (TBM). However, normal staining of the GBM for these 3 chains does not rule out the diagnosis of Alport syndrome.

Electron microscopy

Electron microscopy reveals the characteristic lesions of Alport syndrome. The GBM is irregularly thickened, and the central lamina densa is split and splintered into a heterogeneous network of strands, which enclose electron-lucent areas that may contain microgranulations. The epithelial aspect of the capillary wall is irregular, and epithelial foot processes are fused.

Thickening of the GBM is usually diffuse in adults with Alport syndrome, but in young children with the disorder, the thickening is segmental, and thinning of the basement membrane may be observed or even predominate. The degree of thickening increases with the patient's age and the degree of proteinuria. Therefore, a thick and split GBM is specific for Alport syndrome; however, its absence does not exclude the syndrome, especially in young children. (See the images below.)

If the diagnosis of Alport syndrome remains doubtful after skin or kidney biopsy, screening for genetic mutations may be considered; however, the screening for COL4A3, COL4A4, and COL4A5 mutations is expensive, time consuming, extremely difficult, and not widely available. Moreover, the current detection rate of COL4A5 mutations in relatives with Alport syndrome is only about 50%. At present, therefore, genetic analysis should be restricted to prenatal diagnosis or when uncertainty about diagnosis or mode of transmission of Alport syndrome exists.[22, 23] It is also the only means for diagnosing the carrier state in asymptomatic females with a family history of X-linked Alport syndrome.

No definite treatment exists for Alport syndrome. Research indicates that angiotensin-converting enzyme (ACE) inhibitors can reduce proteinuria and the progression of kidney disease. Thus, the use of ACE inhibitors is reasonable in patients with Alport syndrome who have proteinuria with or without hypertension; the same is true for angiotensin-receptor blockers (ARBs). 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.

A small study by Daina and colleagues found that combination therapy with an ACE inhibitor, an ARB, a non-dihydropyridine calcium channel blocker, and a statin (benazepril, 10-20 mg/day;, valsartan, 80-160 mg/day; diltiazem, 60-120 mg/day; and fluvastatin, 40-80 mg/day), safely ameliorated albuminuria, hypertension, lipid abnormalities, and glomerular selectivity in Alport syndrome patients and halted long-term progression in those without kidney insufficiency. The 4-month study included nine albuminuric adults with Alport syndrome whose creatinine clearance was > 20 ml/min/1.73 m2.[24]

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial of nephroprotective therapy with ramipril in children with Alport syndrome reported that ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)). No safety issues (adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53) were reported.[25]

Some reports suggest that cyclosporine may reduce proteinuria and stabilize kidney function in patients with Alport syndrome; however, the studies were small and uncontrolled. Moreover, reports suggest that patient response to cyclosporine can vary and that the drug may accelerate the development of interstitial fibrosis due to calcineurin-induced nephrotoxicity.[26]

Kidney failure

Begin appropriate replacement therapy as kidney failure advances. Therapy includes the following:

• Erythropoietin for chronic anemia
• Phosphate binders and vitamin D to manage osteodystrophy
• Alkali to correct acidosis
• Antihypertensive therapy to control blood pressure
• Eventually, dialysis; hemodialysis or peritoneal dialysis does not raise specific problems

Pregnancy

In women with the more severe form of Alport syndrome, pregnancy may accelerate the progression to end-stage renal disease (ESRD).

Check 24-hour urinary protein, creatinine, and serum chemistry as follows:

• Annually in patients without renal insufficiency and in those with mild kidney insufficiency
• Every 6 months in patients with moderate kidney insufficiency
• Every 1-3 months in patients with advanced kidney failure

Kidney transplantation is usually offered to patients with Alport syndrome who develop 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 kidney diseases.[27, 4]

However, about 3-5% of male patients with transplants develop anti ̶ glomerular basement membrane (anti-GBM) nephritis. These individuals usually have earl- onset Alport syndrome with clinically significant hearing loss and ESRD by about age 20 years. Female patients with X-linked Alport syndrome (XLAS) and all patients with healthy hearing or late progression to ESRD have a low risk for anti-GBS nephritis.

In view of the excellent graft survival rates and very low incidence of anti-GBM disease, kidney transplantation is not contraindicated in patients with Alport syndrome.[27, 28]

Selection of living related donors for patients with Alport syndrome requires careful consideration of the risk for chronic kidney disease/ESRD on the basis of the genotype. Although molecular genetic analysis is not always possible, mutation identification is very helpful in making informed decisions about living kidney donation.[4]

Consultations with the following clinicians may be necessary:

• Ophthalmologist
• Otorhinolaryngologist
• Transplant surgeon
• Surgeon
• Dialysis specialist
• Nephrologist
• Audiologist
• Genetic counselor

The Alport Variant Collaborative have released the following guidelines for the molecular diagnosis of Alport syndrome[29] :

• Comprehensive parallel genetic testing of the entire coding sequence of each gene is recommended for detection of the causative pathogenic variant in the  COL4A5,  COL4A3 and  COL4A4 genes.
• Genetic testing for diagnosis should take precedence over kidney biopsy.
• When a causative variant is demonstrated, a kidney biopsy may not be needed for diagnosis.
• Multigene Massively Parallel Sequencing kidney disease panels for the extended Alport phenotypes should include COL4A3–COL4A5 

In 2020, the Alport syndrome research collaborative updated its 2013 guidelines. The initiation of treatment with angiotensin-converting enzyme inhibition at the time of diagnosis in males with X-linked Alport syndrome and in males and females with autosomal recessive Alport syndrome is now recommended. For females with X-linked Alport syndrome and males and females with autosomal dominant Alport syndrome, treatment should be initiated at the onset of microalbuminuria.[30]  

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.

In a randomized study comparing the long-term use of losartan (an ARB) with that of enalapril (an ACE inhibitor) in the treatment of proteinuria in children with Alport syndrome, Webb et al found both drugs to be effective and well tolerated. The investigators studied protein levels and kidney function in 27 children with Alport syndrome, following urinary protein ̶ to-creatinine ratios and estimated glomerular filtration rates for up to 3 years. Initial proteinuria decreases in the losartan patients were maintained over the follow-up period, while the enalapril patients not only maintained initial decreases but experienced additional reductions in proteinuria over the 3 years. The incidence of adverse events was low for both sets of patients.[31]

Some small, uncontrolled studies have indicated that cyclosporine may reduce proteinuria and stabilize kidney function in patients with Alport syndrome. Nonetheless, there is also evidence to suggest that patient response to cyclosporine can vary and that the drug may accelerate the development of interstitial fibrosis.[26]

Class Summary

These agents help to reduce proteinuria by decreasing intraglomerular pressure. Moreover, by inhibiting the conversion of angiotensin I to angiotensin II, a growth factor that is implicated in glomerular sclerosis, these drugs have a potential role in slowing sclerotic progression.

Enalapril (Vasotec)

Enalapril is a competitive inhibitor of ACE. By preventing the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, it increases levels of plasma renin and reduces aldosterone secretion.

Fosinopril

A competitive inhibitor of ACE, fosinopril reduces angiotensin II levels, decreasing aldosterone secretion.

Lisinopril (Zestril, Prinivil)

A competitive inhibitor of ACE, lisinopril reduces angiotensin II levels, decreasing aldosterone secretion.

Quinapril (Accupril)

A competitive inhibitor of ACE, quinapril reduces angiotensin II levels, decreasing aldosterone secretion.

Class Summary

ARBS help to reduce proteinuria by decreasing intraglomerular pressure. As with ACE inhibitors, these drugs inhibit the production of angiotensin II, giving them a potential role in slowing the progression of glomerular sclerosis. Unlike ACE inhibitors, however, ARBs do not activate bradykinin and are less likely to be associated with cough and angioedema.

Losartan (Cozaar)

Losartan can be used in patients who are unable to tolerate ACE inhibitors. It is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. Losartan may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors do. Unlike ACE inhibitors, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Candesartan (Atacand)

Candesartan can be used in patients who are unable to tolerate ACE inhibitors. It is a nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. Candesartan may induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors do. Unlike ACE inhibitors, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema.

Valsartan (Diovan)

Valsartan is appropriate for patients unable to tolerate ACE inhibitors. It may induce a more complete inhibition of the RAAS than do ACE inhibitors, it does not affect the response to bradykinin, and it is less likely to be associated with cough and angioedema. Compared with ACE inhibitors (eg, captopril, enalapril), losartan is associated with a lower incidence of drug-induced cough, rash, and taste disturbances.

Class Summary

Cyclosporine may reduce proteinuria and retard the progression of renal disease by inducing afferent arteriolar vasoconstriction, increasing glomerular permselectivity, and inhibiting proinflammatory lymphokines. Efficacy of this treatment in patients was documented only in small series, and further studies are required before this therapy can be recommended on a routine basis. Abstracts suggest that cyclosporine may accelerate the development of interstitial fibrosis.[26, 32] Therefore, such therapy should be approached with caution and close monitoring.

Cyclosporine (Neoral, Sandimmune, Gengraf)

Cyclosporine is a cyclic polypeptide that suppresses some humoral immunity and, to greater extent, cell-mediated immune reactions.