AUTHOR AND EDITOR INFORMATION

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• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
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INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1927, Cecil A. Alport described 3 generations of a family with combinations of progressive hereditary nephritis and deafness. Alport also noted that hematuria was the most common presenting symptom, and that males were affected more severely than females. Subsequently, many more families were described, and the eponym Alport syndrome (AS) was coined in 1961.

Since that time, identification of genetic loci involved in AS has confirmed that the disease is genetically heterogeneous and is caused by defects in one of several subunits of type IV collagen, a major component of basement membranes. In most patients, the disease is inherited as an X-linked trait; however, some families have autosomal recessive and autosomal dominant forms. Furthermore, different mutations in type IV collagen genes can lead to a broad spectrum of disease phenotypes. For example, some families with AS may have normal hearing or minimal hearing defects despite advanced renal disease.

Ultrastructural findings are diagnostic and consist of profound glomerular basement membrane (GBM) abnormalities. No specific treatment exists for patients with AS. Patients who develop end-stage renal disease (ESRD) are offered renal transplantation and usually have excellent allograft survival rates.

Pathophysiology

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), as follows:

• 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, COL4A4, respectively) and are located on chromosome 2.
• Genes COL4A5 and COL4A6 on the X chromosome encode alpha-5 (IV) and alpha-6 (IV) chains, respectively (see Table 1).

Table 1. Location and Mutations of the Genes Coding for Alpha (IV) Chains of Type IV Collagen in AS

* Autosomal recessive AS (mutations spanning 5' regions of COL4A5 and COL4A6 genes)

^† X-linked AS

^‡ Autosomal recessive AS

The alpha-1 (IV) and alpha-2 (IV) chains are ubiquitous in all basement membranes (see Table 2); however, 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 (see Table 2).

Table 2. Tissue Distribution of Alpha (IV) Chains

* Tubular basement membrane

AS 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 AS is 1:5000, and the disorder is genetically heterogeneous. Three genetic forms of AS exist: XLAS, which results from mutations in the COL4A5 gene and accounts for 85% of cases; ARAS, which is caused by mutations in either the COL4A3 or the COL4A4 gene and is responsible for approximately 10-15% of cases; and, rarely, autosomal dominant AS (ADAS), which is caused by mutations in either the COL4A3 or the COL4A4 gene in at least some families and accounts for the remainder of cases (see Table 1).

In the COL4A5 genes from the families with XLAS, more than 300 gene mutations have been reported. Most COL4A5 mutations are small and include missense mutations, splice-site mutations, and small (ie, <10–base pair [bp]) deletions. Approximately 20% of the mutations are major rearrangements at the COL4A5 locus (ie, large-sized 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 AS, 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, inframe deletion, and splicing mutations. ADAS is more rare than XLAS or ARAS. Recently, a splice site mutation resulting in skipping of exon 21 in the COL4A3 gene was found in ADAS.

Despite remarkable advances in delineating the molecular genetics of AS, the pathogenesis of renal failure in patients with this disease remains poorly understood. The primary abnormality in patients with AS results from aberration of basement membrane expression of alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen. These chains are usually underexpressed or absent from the basement membranes of patients with AS.

The primary abnormality in patients with AS 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. Incidentally, the antigen involved in the pathogenesis of Goodpasture syndrome resides in the NC1 domain of the alpha-3 (IV) chain.

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 by 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 AS, limits formation of the collagen network and prevents incorporation of the other collagen chains.

Recent evidence demonstrates that isoform switching of type IV collagen becomes developmentally arrested in patients with XLAS. This leads to retaining of the fetal distribution of alpha-1 (IV) and alpha-2 (IV) isoforms and 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 susceptibility to proteolytic enzymes, leading to basement membrane splitting and damage.

How the defect of collagen chains results in glomerulosclerosis remains unclear. Evidence now suggests that accumulation of types V and VI collagen (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.

Frequency

United States

AS is a rare disease and accounts for approximately 3% of children and 0.2% of adults with ESRD.

International

In Europe, AS accounts for 0.6% of patients with ESRD.

Mortality/Morbidity

AS is a progressive disease that ultimately leads to renal failure. Prognosis depends on the type of inheritance, the sex of the patient, and the type of mutations in type IV collagen genes.

• Approximately 90% of patients with AS develop ESRD by age 40 years. Approximately 75% of patients younger than 30 years develop ESRD (ie, juvenile type).
• Renal prognosis depends on the kind of mutation. The probability of ESRD occurring in patients younger than 30 years is significantly higher (90%) when they have a large rearrangement of the COL4A5 gene compared to 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.
• Prognosis in females with XLAS is usually benign, and they rarely develop ESRD. The reported probability of females with XLAS developing ESRD is 12% by age 40 years and 30% by age 60 years. Risk factors for progression to ESRD are episodes of gross hematuria in childhood, nephrotic range proteinuria, and diffuse GBM thickening visible with electron microscope.

Sex

In patients with XLAS, the disease is consistently severe in males and is much less severe in females. ARAS is equally severe in male and female homozygotes.

Age

• Hematuria is usually discovered during the first years of life in males with AS. If individuals do not have hematuria during the first decade of life, they are unlikely to have AS.
• Proteinuria is usually absent in childhood, but this condition eventually develops in males with XLAS and in both males and females with ARAS.
• Hearing loss and ocular abnormalities are never present at birth and usually become apparent by late childhood or early adolescence, generally before the onset of renal failure.

CLINICAL

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History

Clinical features are best described in patients with XLAS. In these patients, the disease is consistently severe in males and is much less symptomatic in females. In patients with ARAS, the disease is equally severe in male and female homozygotes. Occasionally, mild clinical manifestations are observed in the carriers (heterozygotes) of ARAS.

• Renal manifestations
• • Hematuria: Gross or microscopic hematuria is the most common and earliest manifestation of AS. 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 AS.
  • Proteinuria: Proteinuria is usually absent in childhood but eventually develops in males with XLAS and in both 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 renal failure.
• Hearing defects: Sensorineural deafness is a characteristic feature observed frequently, but not universally, in patients with AS. Some families with AS have severe nephropathy but normal hearing. Hearing loss is never present at birth. Usually, hearing loss becomes apparent by late childhood or early adolescence, generally before the onset of renal failure. Hearing impairment is always associated with renal involvement.
• Ocular manifestations
• • Anterior lenticonus: This condition occurs in approximately 25% of patients with XLAS and is not present at birth, but it worsens with increasing age. Anterior lenticonus is the pathognomonic feature of AS and manifests by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently. This condition is not accompanied by eye pain, redness, or night blindness. No defect in color vision occurs.
  • Dot-and-fleck retinopathy: The most common ocular manifestation of patients with AS, ie, dot-and-fleck retinopathy, occurs in approximately 85% of males with XLAS. This condition is rarely observed in childhood, and it usually becomes apparent at the onset of renal failure. Dot-and-fleck retinopathy is usually asymptomatic with no associated visual impairment or night blindness.
  • Posterior polymorphous corneal dystrophy: This condition is a rare ocular manifestation in patients with AS. Most patients are asymptomatic; however, some patients may develop slowly progressive visual impairment.
• Leiomyomatosis: Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in some families with AS. 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 scanning or magnetic resonance imaging.
• ARAS: ARAS is much less common than XLAS, accounting for 10-15% of all patients with AS. ARAS is usually observed in consanguineous marriages. 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. Renal failure may have an earlier onset. Dot-and-fleck retinopathy and anterior lenticonus also occur in patients with ARAS.
• ADAS: This form of AS is rare and is present in successive generations. Males and females are often equally and severely affected. Renal manifestations and deafness are usually identical to those occurring in patients with XLAS, but renal failure may occur at a later age. Clinical features confined to ADAS include bleeding tendency, macrothrombocytopenia, abnormalities of platelet aggregation (Epstein syndrome), and, occasionally, neutrophil inclusions that resemble Dohle bodies (ie, May-Hegglin anomaly, Fechner syndrome).

Physical

Initially, the findings on physical examination may be unremarkable, but, with time, patients develop progressive renal failure manifested by hypertension, edema, and anemia. Moreover, various extrarenal features may also be observed, as follows:

• Sensorineural deafness
• • In the early stages, hearing impairment is detectable only by audiometry, with bilateral hearing loss to high tones in frequency ranging from 2000-8000 hertz (Hz).
  • In males with XLAS and in both 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 late in life. 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 AS, 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 of the inner ear histology in humans with AS. Striking alterations of the stria vascularis of the cochlea are described.
• Characteristic ocular abnormalities
• • Anterior lenticonus: This condition is the conical protrusion of the lens surface 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 occurs in approximately 25% of patients with XLAS. This condition is not present at birth but worsens with age. Anterior lenticonus is the pathognomonic feature of patients with AS, and its presence in any individual is highly suggestive of AS. This condition is a valuable marker of disease severity and is almost invariably accompanied by progressive renal failure and hearing loss. 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. 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 AS, occurring in approximately 85% of males with XLAS. Dot-and-fleck retinopathy is rarely observed in childhood and usually becomes apparent at the onset of renal failure. This condition comprises numerous, bilateral, white and yellow perimacular dots and flecks. These spare fovea but can spread to the periphery. No associated visual impairment or night blindness occurs. Typically, this condition 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 AS 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 manifestation of patients with AS, this condition appears 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 asymmetric. Posterior polymorphous corneal dystrophy is attributed to the lamellation and thickening of the outer layer of the Descemet membrane. The demonstration of posterior polymorphous corneal dystrophy in any individual is highly suggestive of AS.
• Leiomyomatosis
• • Diffuse leiomyomatosis of the esophagus and tracheobronchial tree has been reported in about 20 families with AS. All patients with AS diffuse leiomyomatosis complex have been found to have deletions that span the 5' ends of the COL4A5 and COL4A6 genes.
  • Females in these families typically exhibit genital leiomyomas with clitoral hypertrophy and variable involvement of the labia majora and uterus. Bilateral posterior subcapsular cataracts also frequently occur in the affected individuals.

Causes

AS is caused by defects in the genes encoding alpha-3 (IV), alpha-4 (IV), or alpha-5 (IV) chains of type IV collagen of the basement membranes.

• The 3 genetic forms of AS are as follows:
• • XLAS - The most common form (85%) that results from mutations in the encoding of the alpha-5 (IV) chain of type IV collagen
  • ARAS - Caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains and is responsible for approximately 10-15% of cases
  • ADAS - Rare form that is caused by mutations in genes encoding either alpha-3 (IV) or alpha-4 (IV) chains

DIFFERENTIALS

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Other Problems to be Considered

Immunoglobulin A nephropathy

Thin GBM disease

Rarely, pulmonary-renal syndrome with antibodies directed against the alpha-2 NC1 domain of type IV collagen may be a manifestation of X-linked AS of thin GBM disease.

WORKUP

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Lab Studies

• Urinalysis: 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.
• Hematuria: Urinary sediment frequently reveals dysmorphic red blood cells and red blood cell casts. Whenever possible, screening of the first-degree relatives for microscopic hematuria of glomerular origin should be performed.
• Proteinuria: Proteinuria is usually absent in early childhood, but it eventually develops. Proteinuria usually progresses with age and can be in the nephrotic range in as many as 30% of patients.

Imaging Studies

• Renal ultrasound: In early stages, a renal ultrasound shows healthy-sized kidneys; however, with advancing renal failure, the kidneys become smaller and echogenic.

Other Tests

• Genetic analysis: If diagnosis 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 AS is only about 50%; thus, for now, genetic analysis should be restricted for prenatal diagnosis or when uncertainty about diagnosis or mode of transmission of AS exists.

Procedures

• Biopsy: Obtain tissue from the kidneys and skin to reveal ultrastructural abnormalities.
• • Skin biopsy is less invasive than renal biopsy and should be obtained first.
  • Kidney biopsy most often provides the diagnosis if it is not established by skin biopsy.

Histologic Findings

The absence of alpha-5 (IV) chains of type IV collagen 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. Thus, the presence of alpha-5 (IV) chain in the epidermal basement membrane indicates a mutation in the alpha-5 (IV) chain that permits its expression in skin but not in the kidney in XLAS, ARAS, or another disorder.

Findings on light microscopy of kidney biopsy specimens contribute little toward the diagnosis. The findings are nonspecific and 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 directed against alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains of type IV collagen can be used to evaluate the GBM for the presence or absence of these chains. The absence of these chains from the GBM is diagnostic of AS and has not been described in any other condition. In addition, renal expression of type IV collagen alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains can differentiate XLAS and ARAS. In most patients with XLAS, alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) 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 TBM; however, normal staining of the GBM for alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains does not rule out the diagnosis of AS.

Electron microscopy reveals diffuse thickening and splitting of the basement membrane in 60-90% of patients. Diffuse thinning is observed in some patients with AS. A normal ultrastructure of the GBM makes a diagnosis of AS highly unlikely.

TREATMENT

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Medical Care

No definite treatment exists for AS. Data from animal studies suggest benefits from angiotensin-converting enzyme (ACE) inhibitors in the reduction of proteinuria and progression of renal disease; thus, the use of ACE inhibitors is reasonable in patients with AS who have proteinuria with or without hypertension. Some reports suggest that cyclosporine may reduce proteinuria and stabilize renal functions in patients with AS; however, the studies were small and uncontrolled. Larger and controlled studies are needed to define the role of cyclosporine in AS.

Gene therapy for Alport syndrome is being studied. Animal studies are underway to evaluate the delivery of human alpha-5 (IV) chain of GBM in a canine model of X-linked Alport syndrome.

Surgical Care

Renal transplantation is usually offered to patients with AS who develop ESRD. The allograft survival rate in these patients is similar to patients with other renal diseases. Recurrent disease does not occur in the transplant; however, approximately 3-5% of patients with AS who undergo transplant develop anti-GBM nephritis. In view of excellent graft survival rates and a very low incidence of anti-GBM disease, renal transplantation is not contraindicated in patients with AS.

Consultations

• Ophthalmologist
• Otorhinolaryngologist
• Transplant surgeon
• Surgeon
• Dialysis specialist

Diet

Patients require a renal failure diet once ESRD ensues.

MEDICATION

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ACE inhibitors or angiotensin-receptor blockers (ARBs) should be administered to patients with AS who have proteinuria with or without hypertension.

Drug Category: ACE inhibitors

Help to reduce proteinuria by decreasing intraglomerular pressure; moreover, angiotensin II is a growth factor that is implicated in glomerular sclerosis. By inhibiting angiotensin II, these drugs have a potential role in slowing down glomerular sclerosis.

Drug Category: Angiotensin-receptor blockers

Help reduce proteinuria by decreasing the intraglomerular pressure. By inhibiting angiotensin II, these drugs have a potential role in slowing down glomerular sclerosis, as with ACE inhibitors. Unlike ACE inhibitors, ARBs do not activate bradykinin and are not associated with cough and angioedema.

FOLLOW-UP

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Further Outpatient Care

• Control the patient's blood pressure.
• Administer ACE inhibitors or ARBs to control proteinuria.
• Monitor renal function test results and proteinuria (24-h urinary protein and creatinine). Check 24-hour urinary protein, creatinine, and serum chemistry on an annual basis in those patients without renal insufficiency or those with mild renal insufficiency, every 6 months in those patients with moderate renal insufficiency, and every 1-3 months in those patients with advanced renal failure.

In/Out Patient Meds

• Administer ACE inhibitors or ARBs to control proteinuria and hypertension.

Transfer

• Transfer to a dialysis facility when the patient develops ESRD.

Complications

• Progression of renal failure: The risk of progression of renal failure is highest among males with XLAS and in both males and females with ARAS. ESRD develops in virtually all males with XLAS. Approximately 90% of patients develop ESRD by age 40 years. According to the age at ESRD, XLAS arbitrarily is either the juvenile type or the adult type with a cut off at age 30 years. The juvenile type is encountered in 75% of kindreds. Renal prognosis depends on the kind of mutation. The probability of ESRD in people younger than 30 years is significantly higher (90%) in patients with large rearrangement of the COL4A5 gene compared to 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.

  Prognosis in females with XLAS is usually benign, and they rarely develop ESRD. The reported probability of developing ESRD in these patients is 12% by age 40 years and 30% by age 60 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.

• 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, Fechner 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.

Prognosis

• Renal prognosis depends on the kind of mutation. Approximately 90% of patients with AS develop ESRD by age 40 years. The probability of ESRD in people younger than 30 years is significantly higher in patients with a large rearrangement of the COL4A5 gene compared to those with minor mutations. Prognosis in females with XLAS is usually benign, with only 12% developing ESRD by age 40 years and 30% by age 60 years.

Patient Education

• Provide pre-ESRD education to discuss various options and issues regarding renal replacement therapy (eg, dialysis, transplantation).
• Arrange dietary counseling for patients approaching ESRD.
• Avoid administering nephrotoxins in these patients, including over-the-counter nonsteroidal analgesic agents.
• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Blood in the Urine.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Erroneous determination of the mode of inheritance of Alport syndrome can lead to potential adverse consequences such as unnecessary medical termination of pregnancy. In these situations, a firm diagnosis and mode of inheritance of Alport syndrome by genetic analysis is needed to provide information essential for determining prognosis and guiding genetic counseling. This also underscores the need for trained medical geneticists to interpret complex inheritance modes in clinical situations where genetic heterogeneity exists in human Mendelian diseases.

Special Concerns

• Anti-GBM disease in patients with AS who receive a renal transplant
• • Approximately 3-5% of patients who received a transplant develop anti-GBM nephritis. These patients possess circulating antibodies that are directed against the NC1 component of the alpha-3 (IV) chain of type IV collagen, similar to that in Goodpasture syndrome. This antigen is not expressed in the native kidneys of patients with AS but is present in the transplanted kidney and is recognized as a foreign antigen by the recipient's immune system.
  • Only a few patients develop anti-GBM disease after transplantation; the cause remains unclear. At present, the only way to determine whether a patient with AS will develop posttransplant anti-GBM nephritis is to perform the transplant; however, certain patients are at very low risk for developing posttransplant anti-GBM nephritis, including patients with normal hearing, patients with late progression to ESRD, or females with XLAS.
  • Posttransplant anti-GBM nephritis usually develops within the first year of the transplant. 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 AS 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.
  • 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 AS; however, in patients who have already lost an allograft from posttransplant anti-GBM nephritis, the optimal management is uncertain because of the high likelihood of recurrence and subsequent allograft loss.

MULTIMEDIA

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Media file 1:  Electron micrograph of kidney biopsy from a patient with Alport syndrome (AS). Note the splitting and lamellation of the glomerular basement membrane (see arrows).
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
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• References

• Alport AC. Hereditary familial congenital haemorrhagic nephritis. Br Med J. 1927;1:504-6.
• Brainwood D, Kashtan C, Gubler MC. Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation. Kidney Int. Mar 1998;53(3):762-6. [Medline].
• Callis L, Vila A, Carrera M. Long-term effects of cyclosporine A in Alport''s syndrome. Kidney Int. Mar 1999;55(3):1051-6. [Medline].
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Article Last Updated: Jan 30, 2007