Alport Syndrome[1]

Alport SyndromeAlport Syndrome

Nephrology Grand RoundsNephrology Grand RoundsSeptember 22September 22ndnd, 2009, 2009

Aditya Mattoo, MDAditya Mattoo, MD

ObjectivesObjectives HistoryHistory BackgroundBackground PathophysiologyPathophysiology Inheritance PatternsInheritance Patterns Clinical FindingsClinical Findings DiagnosisDiagnosis TreatmentTreatment PrognosisPrognosis

HistoryHistory

HistoryHistory Dr. Leonard Guthrie in 1902, described a family with members who Dr. Leonard Guthrie in 1902, described a family with members who

had hematuria that “may vary in extent, liable to paroxysmal had hematuria that “may vary in extent, liable to paroxysmal exacerbations with influenza-like symptoms, and not marked by exacerbations with influenza-like symptoms, and not marked by edema.” edema.”

He called the syndrome congenital hereditary family hematuria, He called the syndrome congenital hereditary family hematuria,

none of the affected individuals exhibited evidence of chronic renal none of the affected individuals exhibited evidence of chronic renal damage at the time.damage at the time.

Arthur Frederick Hurst in 1923 described the development of Arthur Frederick Hurst in 1923 described the development of uremia in several members of this family. uremia in several members of this family.

In 1927, Dr. Cecil Alport followed 3 later generations of the same In 1927, Dr. Cecil Alport followed 3 later generations of the same family and he recognized that deafness was a syndromic component family and he recognized that deafness was a syndromic component and that the disorder tended to be more severe in males than and that the disorder tended to be more severe in males than females, that affected males died of uremia, while females lived to females, that affected males died of uremia, while females lived to old age. old age.

Subsequently, many more families were described and the disease Subsequently, many more families were described and the disease was named Alport Syndrome (AS) in 1961.was named Alport Syndrome (AS) in 1961.

LB GuthrieLB Guthrie”Idiopathic,” or congenital, hereditary and familial haematuria.”Idiopathic,” or congenital, hereditary and familial haematuria.Lancet, London, 1902, 1: 1243-1246. Lancet, London, 1902, 1: 1243-1246.

AF Hurst:AF Hurst:Hereditary familial congenital haemorrhagic nephritis occurring in sixteen individuals in three generations. Hereditary familial congenital haemorrhagic nephritis occurring in sixteen individuals in three generations. Guy’s Guy’s Hosp Rec, 1923, 3: 368-370Hosp Rec, 1923, 3: 368-370

C Alport: C Alport: Hereditary familial congenital haemorrhagic nephritis.Hereditary familial congenital haemorrhagic nephritis. British Medical Journal, London, 1927, I: 504-506. British Medical Journal, London, 1927, I: 504-506.

BackgroundBackground

BackgroundBackground The incidence of AS is approximately 1 in The incidence of AS is approximately 1 in

5000 births.5000 births.

In the US, accounts for approximately 3% In the US, accounts for approximately 3% of children and 0.2% of adults with ESRD.of children and 0.2% of adults with ESRD.

In Europe, the incidence AS is greater In Europe, the incidence AS is greater and accounts for 0.6% of patients with and accounts for 0.6% of patients with ESRD.ESRD.

PathophysiologyPathophysiology

PathophysiologyPathophysiology AS is a primary basement membrane disorder AS is a primary basement membrane disorder

arising from mutations in genes encoding arising from mutations in genes encoding several members of the type IV collagen several members of the type IV collagen family.family.

Basement membranes are assembled through Basement membranes are assembled through an interweaving of type IV collagen with an interweaving of type IV collagen with laminins and sulfated proteoglycans.laminins and sulfated proteoglycans.

Six genes, Six genes, COL4A1, COL4A2, COL4A3, COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 COL4A4, COL4A5 andand COL4A6 COL4A6 encode the six encode the six chains of collagen IV, α1(IV) through α6(IV), chains of collagen IV, α1(IV) through α6(IV), respectively.respectively.

PathophysiologyPathophysiology Each collagen IV chain has three domains:Each collagen IV chain has three domains:

Short 7S domain at the N-terminalShort 7S domain at the N-terminal A long, collagenous domain occupying the midsection of the A long, collagenous domain occupying the midsection of the

moleculemolecule Noncollagenous domain (NC1) positioned at the C terminalNoncollagenous domain (NC1) positioned at the C terminal

Despite the many potential permutations, the six collagen Despite the many potential permutations, the six collagen IV chains only form three sets of triple helical molecules IV chains only form three sets of triple helical molecules called protomers: α1.α1.α2(IV), α3.α4.α5(IV) and called protomers: α1.α1.α2(IV), α3.α4.α5(IV) and α5.α5.α6(IV).α5.α5.α6(IV).

PathophysiologyPathophysiology Two NC1 trimers unite Two NC1 trimers unite

to form a hexamer.to form a hexamer. Four 7S domains form Four 7S domains form

tetramers with other tetramers with other protomersprotomers

The three protomers only The three protomers only form three sets of form three sets of hexamers to form hexamers to form collagenous networks:collagenous networks: α1.α1.α2(α1.α1.α2(IVIV) - α1.α1.α2() - α1.α1.α2(IVIV)) α3.α4.α5(α3.α4.α5(IVIV) – ) –

α3.α4.α5(α3.α4.α5(IVIV)) α1.α1.α2(α1.α1.α2(IVIV) – ) –

α5.α5.α6(α5.α5.α6(IVIV))

Inheritance Inheritance PatternsPatterns

Inheritance PatternsInheritance Patterns Three genetic forms of AS exist: Three genetic forms of AS exist:

XLAS, which results from mutations in the XLAS, which results from mutations in the COL4A5COL4A5 gene and accounts for 80-85% of cases. gene and accounts for 80-85% of cases.

ARAS, which is caused by mutations in either the ARAS, which is caused by mutations in either the COL4A3COL4A3 or the or the COL4A4COL4A4 gene and is responsible gene and is responsible for approximately 10-15% of cases.for approximately 10-15% of cases.

Rarely ADAS, which is also caused by a mutation Rarely ADAS, which is also caused by a mutation in either the in either the COL4A3COL4A3 or the or the COL4A4COL4A4 gene gene accounts for the remainder of cases.accounts for the remainder of cases.

It is unclear why some heterozygous It is unclear why some heterozygous mutations cause ARAS with progressive mutations cause ARAS with progressive renal disease, while others are associated renal disease, while others are associated with thin basement nephropathy, which is with thin basement nephropathy, which is typically benign.typically benign.

No mutations have been identified solely in No mutations have been identified solely in the the COL4A6COL4A6 gene. gene.

Inheritance PatternsInheritance Patternsα Chain Genes Chromosome Tissue Distribution Mutation

α1(IV) COL4A1 13 Ubiquitous Unknown

α2(IV) COL4A2 13 Ubiquitous Unknown

α3(IV) COL4A3 2GBM, tubular basement membrane, Descemet

membrane, Bruch membrane, anterior lens capsule, lungs, cochlea

ARAS*/ADAS**

α4(IV) COL4A4 2 GBM, TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea ARAS/ADAS

α5(IV) COL4A5 X

Epidermal basement membrane (EBM), Bowman’s capsule (BC), GBM, distal TBM, Descemet membrane, Bruch membrane, anterior lens capsule, lungs, cochlea

XLAS†

α6(IV) COL4A6 X BC, TBM, EBM Leiomyomatosis‡

*Autosomal recessive Alport syndrome, ** Autosomal dominant AS† X-linked AS‡ ARAS with mutations spanning COL4A5 and COL4A6 genes

X Linked MutationsX Linked Mutations In the In the COL4A5COL4A5 genes from the families with XLAS, genes from the families with XLAS,

more than 300 gene mutations have been reported. more than 300 gene mutations have been reported.

Most Most COL4A5COL4A5 mutations are small and include mutations are small and include missense mutations, splice-site mutations, and small missense mutations, splice-site mutations, and small deletions where renal failure and deafness occur deletions where renal failure and deafness occur after 30 years of age (adult form). after 30 years of age (adult form).

Approximately 20% of the mutations are major Approximately 20% of the mutations are major rearrangements at the rearrangements at the COL4A5COL4A5 locus (i.e., large locus (i.e., large deletions, reading frame shifts, etc) in which patients deletions, reading frame shifts, etc) in which patients are symptomatic before the age of 30 (juvenile form).are symptomatic before the age of 30 (juvenile form).

A rare of deletion spanning A rare of deletion spanning COL4A5COL4A5 and and COL4A6COL4A6 genes is associated with a combination of XLAS and genes is associated with a combination of XLAS and diffuse leiomyomatosis.diffuse leiomyomatosis.

Autosomal MutationsAutosomal Mutations To date, only 6 mutations in the To date, only 6 mutations in the COL4A3COL4A3

gene and 12 mutations in the gene and 12 mutations in the COL4A4COL4A4 gene gene have been identified in patients with ARAS. have been identified in patients with ARAS.

ARAS patients are either homozygous or ARAS patients are either homozygous or compound heterozygous for their mutations, compound heterozygous for their mutations, and their parents are usually asymptomatic and their parents are usually asymptomatic carriers.carriers.

ADAS is more rare than XLAS or ARAS and ADAS is more rare than XLAS or ARAS and is a result of a dominant negative mutation is a result of a dominant negative mutation of the of the COL4A3COL4A3 or or COL4A4 COL4A4 genes whose gene genes whose gene product acts antagonistically to the wild-type product acts antagonistically to the wild-type allele.allele.

Embryonic DevelopmentEmbryonic Development Recent evidence demonstrates that isoform Recent evidence demonstrates that isoform

switching of type IV collagen becomes switching of type IV collagen becomes developmentally arrested in patients with AS.developmentally arrested in patients with AS.

In normal embryogenesis, oxidative and In normal embryogenesis, oxidative and physical stress stimulates the replacement of physical stress stimulates the replacement of αα1.1.αα1.1.αα2(IV) with 2(IV) with αα3.3.αα4.4.αα5(IV) network.5(IV) network.

The cysteine-rich The cysteine-rich αα3.3.αα4.4.αα5(IV) chains are 5(IV) chains are thought to enhance the resistance of GBM to thought to enhance the resistance of GBM to proteolytic degradation at the site of proteolytic degradation at the site of glomerular filtration. glomerular filtration.

Thus, anomalous persistence of Thus, anomalous persistence of αα1.1.αα1.1.αα2(IV) 2(IV) isoforms confers an unexpected increase in isoforms confers an unexpected increase in susceptibility to proteolytic enzymes, leading susceptibility to proteolytic enzymes, leading to basement membrane splitting and damage.to basement membrane splitting and damage.

Embryonic DevelopmentEmbryonic Development

Clinical FindingsClinical Findings

Clinical FindingsClinical Findings In patients with XLAS, the disease is In patients with XLAS, the disease is

consistently severe in males and female consistently severe in males and female carriers are generally less symptomatic.carriers are generally less symptomatic.

The female carrier variable phenotype is due The female carrier variable phenotype is due to lyonization by which only one X to lyonization by which only one X chromosome is active per cell. chromosome is active per cell.

In patients with ARAS, the disease is equally In patients with ARAS, the disease is equally severe in male and female homozygotes and severe in male and female homozygotes and the course is similar to that of XLAS. the course is similar to that of XLAS.

In ADAS, the renal manifestations are In ADAS, the renal manifestations are typically milder and present later than XLAS typically milder and present later than XLAS and ARAS. and ARAS.

Renal Manifestations - Renal Manifestations - HematuriaHematuria

Gross or microscopic hematuria is the most Gross or microscopic hematuria is the most common and earliest manifestation. common and earliest manifestation.

Microscopic hematuria is observed usually in Microscopic hematuria is observed usually in the first few years of life in all males and in the first few years of life in all males and in 95% of females. 95% of females.

Hematuria is usually persistent in males, Hematuria is usually persistent in males, whereas it can be intermittent in females. whereas it can be intermittent in females.

Like IgA nephropathy, approximately 60-70% Like IgA nephropathy, approximately 60-70% of patients experience episodes of gross of patients experience episodes of gross hematuria, often precipitated by upper hematuria, often precipitated by upper respiratory infection, during the first 2 respiratory infection, during the first 2 decades of life. decades of life.

Renal Manifestations - Renal Manifestations - ProteinuriaProteinuria

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

Significant proteinuria is infrequent in Significant proteinuria is infrequent in female carriers with XLAS, but it may female carriers with XLAS, but it may occur.occur.

Proteinuria usually progresses with age and Proteinuria usually progresses with age and can be in the nephrotic range in as many as can be in the nephrotic range in as many as 30% of patients.30% of patients.

Renal Manifestations - Renal Manifestations - ESRDESRD

The risk of progression of renal failure is The risk of progression of renal failure is highest among males with XLAS and in both highest among males with XLAS and in both males and females with ARAS. males and females with ARAS.

ESRD develops in virtually all males with ESRD develops in virtually all males with XLAS, usually between the ages of 16 and 35 XLAS, usually between the ages of 16 and 35 years. years.

Some evidence suggests that ESRD may Some evidence suggests that ESRD may occur even earlier in ARAS, whereas renal occur even earlier in ARAS, whereas renal failure has a slower progression in ADAS.failure has a slower progression in ADAS.

Approximately 90% of patients develop ESRD Approximately 90% of patients develop ESRD by age 40 years. by age 40 years.

The probability of ESRD in people younger The probability of ESRD in people younger than 30 years is significantly higher (90%) in than 30 years is significantly higher (90%) in patients with large rearrangements of the patients with large rearrangements of the COL4A5COL4A5 gene compared to those with minor gene compared to those with minor mutations (50-70%).mutations (50-70%).

ESRD – Female CarriersESRD – Female Carriers The prognosis in females carriers with XLAS is The prognosis in females carriers with XLAS is

usually benign, and they develop ESRD at usually benign, and they develop ESRD at much lower rates. much lower rates.

The reported probability of developing ESRD in The reported probability of developing ESRD in female carriers is 12% by age 40 years and female carriers is 12% by age 40 years and 30% by age 60 years. 30% by age 60 years.

Risk factors for progression to ESRD are Risk factors for progression to ESRD are episodes of gross hematuria in childhood, episodes of gross hematuria in childhood, hearing loss, nephrotic range proteinuria, and hearing loss, nephrotic range proteinuria, and diffuse GBM lamellations seen on electron diffuse GBM lamellations seen on electron microscopy (EM).microscopy (EM).

Hearing DeficitsHearing Deficits Bilateral sensorineural hearing loss is a Bilateral sensorineural hearing loss is a

characteristic feature observed frequently, characteristic feature observed frequently, but not universally. but not universally.

May reflect impaired adhesion of the Organ May reflect impaired adhesion of the Organ of Corti (which contain auditory sensory cells) of Corti (which contain auditory sensory cells) to the basilar membrane of the inner ear.to the basilar membrane of the inner ear.

About 50% of male patients with XLAS show About 50% of male patients with XLAS show sensorineural deafness by age 25 years, and sensorineural deafness by age 25 years, and about 90% are deaf by age 40 years.about 90% are deaf by age 40 years.

Hearing DeficitsHearing Deficits Hearing loss is never present at birth. Hearing loss is never present at birth. Usually, hearing loss becomes apparent Usually, hearing loss becomes apparent

by late childhood or early adolescence, by late childhood or early adolescence, generally before the onset of renal failure. generally before the onset of renal failure.

Hearing impairment is always associated Hearing impairment is always associated with renal involvement. with renal involvement.

Some families with AS have been found to Some families with AS have been found to have severe nephropathy without hearing have severe nephropathy without hearing loss.loss.

Ocular Findings – Anterior Ocular Findings – Anterior LenticonusLenticonus

Conical protrusion of the central portion Conical protrusion of the central portion of the lens into the anterior chamber.of the lens into the anterior chamber.

It is most marked anteriorly because it is It is most marked anteriorly because it is the region where the capsule is thinnest, the region where the capsule is thinnest, the stresses of accommodation are the stresses of accommodation are greatest, and the lens is least supported.greatest, and the lens is least supported.

Occurs in approximately 15-20% of AS Occurs in approximately 15-20% of AS patients.patients.

Ocular Findings – Anterior Ocular Findings – Anterior LenticonusLenticonus

Pathognomonic feature if found.Pathognomonic feature if found.

Not present at birth, but it develops and Not present at birth, but it develops and worsens with increasing age leading to a worsens with increasing age leading to a slowly progressive deterioration of vision. slowly progressive deterioration of vision.

Not accompanied by eye pain, redness, Not accompanied by eye pain, redness, night blindness or defect in color vision.night blindness or defect in color vision.

Can be complicated by cataract formation.Can be complicated by cataract formation.

Ocular Findings – Anterior Ocular Findings – Anterior LenticonusLenticonus

Ocular Findings – Dot and Ocular Findings – Dot and Fleck RetinopathyFleck Retinopathy

The most common ocular manifestation of AS. The most common ocular manifestation of AS. Occurs in approximately 70% of males with Occurs in approximately 70% of males with

XLAS and about 10% female carriers.XLAS and about 10% female carriers. Small yellow or white granulations scattered Small yellow or white granulations scattered

around the macula or periphery of the retina.around the macula or periphery of the retina. Rarely observed in childhood, and it usually Rarely observed in childhood, and it usually

becomes apparent at the onset of renal becomes apparent at the onset of renal failure.failure.

Usually asymptomatic with no associated Usually asymptomatic with no associated visual impairment or night blindness.visual impairment or night blindness.

Ocular Findings – Dot and Ocular Findings – Dot and Fleck RetinopathyFleck Retinopathy

LeiomyomatosisLeiomyomatosis Diffuse leiomyomatosis of the gastrointestinal, Diffuse leiomyomatosis of the gastrointestinal,

respiratory and female genital tracts has been respiratory and female genital tracts has been reported in some families with AS (particularly reported in some families with AS (particularly esophagus and tracheobronchial tree).esophagus and tracheobronchial tree).

Seen in 2-5% of patients and carriers of XLAS who Seen in 2-5% of patients and carriers of XLAS who have deletions that involve have deletions that involve COL4A5COL4A5 and extend to and extend to the second intron of the adjacent the second intron of the adjacent COL4A6COL4A6 gene. gene.

Symptoms usually appear in late childhood and Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor.dyspnea, cough, and stridor.

DiagnosisDiagnosis

DiagnosisDiagnosis Historical information (family history, Historical information (family history,

hearing loss, visual disturbances, gross hearing loss, visual disturbances, gross hematuria)hematuria)

Tissue biopsy often reveals ultrastructural Tissue biopsy often reveals ultrastructural abnormalities and confirm diagnosis.abnormalities and confirm diagnosis.

Skin biopsy is less invasive than renal Skin biopsy is less invasive than renal biopsy and should be obtained first.biopsy and should be obtained first.

Molecular genetic testing in equivocal Molecular genetic testing in equivocal biopsy cases, patients in whom biopsy is biopsy cases, patients in whom biopsy is contraindicated and prenatal testing.contraindicated and prenatal testing.

Skin BiopsySkin Biopsy

The absence of The absence of αα5(IV) chains in the epidermal basement 5(IV) chains in the epidermal basement membrane on skin biopsy is diagnostic of XLAS.membrane on skin biopsy is diagnostic of XLAS.

However, the absence of However, the absence of αα5(IV) chains in the epidermal 5(IV) chains in the epidermal basement membrane is observed in only 80% of males basement membrane is observed in only 80% of males with XLAS. with XLAS.

Therefore, the presence of Therefore, the presence of αα5(IV) chains in the 5(IV) chains in the epidermal basement membrane does not rule out the epidermal basement membrane does not rule out the diagnosis of XLAS.diagnosis of XLAS.

Furthermore, Furthermore, αα3(IV) and 3(IV) and αα4(IV) chains are not found in 4(IV) chains are not found in the epidermal basement membrane so skin biopsy can the epidermal basement membrane so skin biopsy can not be used for the diagnosis of ARAS and ADAS. not be used for the diagnosis of ARAS and ADAS.

Skin Biopsy - IFSkin Biopsy - IF

A, ARAS. Normal staining of EBM for α5(IV), indistinguishable from normal controls.B, Female carrier of XLAS. Linear staining for α5(IV) on right side, loss of staining on left.C, Male XLAS. No staining for α5(IV) of EBM.

Renal Biopsy - Light Renal Biopsy - Light MicroscopyMicroscopy

Light microscopy Light microscopy findings are nonspecific.findings are nonspecific.

Can see focal and Can see focal and segmental glomerular segmental glomerular hypercellularity of the hypercellularity of the mesangial and mesangial and endothelial cells.endothelial cells.

Renal interstitial foam Renal interstitial foam cells can be found and cells can be found and represent lipid-laden represent lipid-laden macrophages which can macrophages which can be seen in many renal be seen in many renal diseases.diseases.

Renal Biopsy - IFRenal Biopsy - IF Monoclonal antibodies directed Monoclonal antibodies directed

against against αα3(IV), 3(IV), αα4(IV), and 4(IV), and αα5(IV) 5(IV) chains of type IV collagen can be used chains of type IV collagen can be used to evaluate the GBM for the presence to evaluate the GBM for the presence or absence of these chains. or absence of these chains.

The absence of these chains from the The absence of these chains from the GBM is diagnostic of AS and has not GBM is diagnostic of AS and has not been described in any other condition.been described in any other condition.

Renal Biopsy - IFRenal Biopsy - IF

A, TBMN with normal diffuse linear staining for α5(IV), indistinguishable from controls. B, Female carrier of XLAS. Discontinuous staining of GBM and BC.C, ARAS. No GBM staining, but BC and TBM preserved. α3(IV) staining negative (not shown). D, Male XLAS. Staining for α5(IV) completely negative.

Renal Biopsy - EMRenal Biopsy - EM Earliest finding is thinning of GBM.Earliest finding is thinning of GBM. Characteristic finding of longitudinal Characteristic finding of longitudinal

splitting of lamina densa of GBM.splitting of lamina densa of GBM. May not be seen in young AS patients.May not be seen in young AS patients. The proportion of GBM that shows The proportion of GBM that shows

splitting increases from 30% by age splitting increases from 30% by age 10 to more than 90% by age 30.10 to more than 90% by age 30.

Rumpelt, HJ. Hereditary nephropathy: Correlation of clinical data with GBM alterations. Clin Nephrol 1980; 13:203.

Renal Biopsy - EMRenal Biopsy - EM

EM of patient with AS, arrows are pointing to the splitting and EM of patient with AS, arrows are pointing to the splitting and lamellation of the GBM.lamellation of the GBM.

Renal Biopsy - EMRenal Biopsy - EM

EM reveals GBM with lamellation (left) and another segment with EM reveals GBM with lamellation (left) and another segment with thinning (right)thinning (right)

Renal Biopsy - EMRenal Biopsy - EM

A, EM of glomerular basement membrane, showing segments of A, EM of glomerular basement membrane, showing segments of thickening and thinning with irregular contours.thickening and thinning with irregular contours.

B, Magnification of a thickened segment showing lamellation, B, Magnification of a thickened segment showing lamellation, electron-lucent areas and electron-dense granules.electron-lucent areas and electron-dense granules.

TreatmentTreatment

Treatment – Angiotensin Treatment – Angiotensin BlockadeBlockade

It has been proposed, although unproven, that It has been proposed, although unproven, that angiotensin blockade may diminish the rate of angiotensin blockade may diminish the rate of proteinuria leading to glomerulosclerosis and thereby proteinuria leading to glomerulosclerosis and thereby disease progression.disease progression.

To date, only small uncontrolled trials have To date, only small uncontrolled trials have demonstrated the effect of ACE inhibitors on reducing demonstrated the effect of ACE inhibitors on reducing proteinuria in humans.proteinuria in humans.

Preemptive therapy with ACE inhibitors in an Preemptive therapy with ACE inhibitors in an αα3(IV) 3(IV) knockoutknockout Alport mouse model prolonged lifespan until Alport mouse model prolonged lifespan until death from renal failure by more than 100%.death from renal failure by more than 100%.

In the absence of more data, the use of ACE inhibitors In the absence of more data, the use of ACE inhibitors is reasonable in patients with Alport syndrome.is reasonable in patients with Alport syndrome.

Cohen, EP. In hereditary nephritis ACE inihibition decreases proteinuria and may slow the rate of Cohen, EP. In hereditary nephritis ACE inihibition decreases proteinuria and may slow the rate of progression. Am J Kidney Dis, 1996; 27:199.progression. Am J Kidney Dis, 1996; 27:199.

Gross, O et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in Gross, O et al. Preemptive ramipril therapy delays renal failure and reduces renal fibrosis in COL4A3COL4A3-knockout mice with Alport syndrome. KI 2003; 63: 438-446.-knockout mice with Alport syndrome. KI 2003; 63: 438-446.

Treatment - CyclosporineTreatment - Cyclosporine Cyclosporine has also been studied in small Cyclosporine has also been studied in small

uncontrolled trials as well.uncontrolled trials as well.

One study of eight Alport males who One study of eight Alport males who received cyclosporine for a mean duration of received cyclosporine for a mean duration of 8.4 years suggested a slower progression to 8.4 years suggested a slower progression to ESRD as compared to related effected males.ESRD as compared to related effected males.

Another study demonstrated reduction in Another study demonstrated reduction in proteinuria, however, 4 of 9 patients proteinuria, however, 4 of 9 patients exhibited cyclosporine nephrotoxicity.exhibited cyclosporine nephrotoxicity.

Callis, L et al. Long-term effects of cyclosporine A in Alport’s syndrome, KI 1999; 55: 1051-1056Callis, L et al. Long-term effects of cyclosporine A in Alport’s syndrome, KI 1999; 55: 1051-1056 Charbit, M et al. Cyclosporine therapy in patients with Alport syndrome. Pediatric Nephrology 2007; 22:57-Charbit, M et al. Cyclosporine therapy in patients with Alport syndrome. Pediatric Nephrology 2007; 22:57-

63.63.

Treatment – Stem CellsTreatment – Stem Cells Cell based therapies have shown some Cell based therapies have shown some

curative potential in animal models, curative potential in animal models, however, have yet to be tested in humans. however, have yet to be tested in humans.

Two research groups have reported that Two research groups have reported that treating mice with wild-type bone marrow treating mice with wild-type bone marrow derived cells can improve the disease in derived cells can improve the disease in αα3(IV) knockout Alport mice.3(IV) knockout Alport mice.

The bone marrow stem cells differentiated The bone marrow stem cells differentiated into podocytes which then secreted the into podocytes which then secreted the missing missing αα3(IV) chains in this mouse model.3(IV) chains in this mouse model.

Prodromidi, EI et al. Bone marrow-derived cells contribute to podocyte regeneration and amelioration Prodromidi, EI et al. Bone marrow-derived cells contribute to podocyte regeneration and amelioration of renal disease in a mouse model of Alport syndrome. Stem Cells. 2006; 24: 2448-2455.of renal disease in a mouse model of Alport syndrome. Stem Cells. 2006; 24: 2448-2455.

Sugimoto H et al. Bone marrow–derived stem cells repair basement membrane collagen defects and Sugimoto H et al. Bone marrow–derived stem cells repair basement membrane collagen defects and reverse genetic kidney disease. Proc Natl Acad Sci USA 2006; 103:7321-7326.reverse genetic kidney disease. Proc Natl Acad Sci USA 2006; 103:7321-7326.

Treatment – Renal Treatment – Renal TransplantTransplant

AS is essentially cured with renal AS is essentially cured with renal transplantation, and as one would suspect transplantation, and as one would suspect unless the donor has the disease, AS will not unless the donor has the disease, AS will not occur in the transplanted organ.occur in the transplanted organ.

The most significant and devastating, albeit The most significant and devastating, albeit rare, complication of transplantation is rare, complication of transplantation is antiglomerular basement membrane nephritis.antiglomerular basement membrane nephritis.

Approximately 3-5% of patients with Alport Approximately 3-5% of patients with Alport syndrome who receive a transplant develop syndrome who receive a transplant develop anti-GBM antibody to the NC1 component of anti-GBM antibody to the NC1 component of the α3(IV) chain. the α3(IV) chain.

Post-transplant anti-GBM nephritis usually Post-transplant anti-GBM nephritis usually develops within the first year of the transplant.develops within the first year of the transplant.

Treatment – Renal Treatment – Renal TransplantTransplant

For unclear reasons, certain patients are at very low For unclear reasons, certain patients are at very low risk for developing post-transplant anti-GBM nephritis, risk for developing post-transplant anti-GBM nephritis, including patients with normal hearing, patients with including patients with normal hearing, patients with late progression to ESRD, or females with XLAS.late progression to ESRD, or females with XLAS.

Unlike de novo anti-GBM nephritis, pulmonary Unlike de novo anti-GBM nephritis, pulmonary hemorrhage is never observed because the patient's hemorrhage is never observed because the patient's lung tissue does not contain the antigen. lung tissue does not contain the antigen.

Treatment with plasmapheresis and cyclophosphamide Treatment with plasmapheresis and cyclophosphamide is usually unsuccessful, and most patients lose the is usually unsuccessful, and most patients lose the allograft.allograft.

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

Kashtan CE. Alport syndrome and thin glomerular basement membrane disease. Kashtan CE. Alport syndrome and thin glomerular basement membrane disease.  J Am Soc NephrolJ Am Soc Nephrol. 1998;9:1736.. 1998;9:1736.

Thank you.Thank you.