Alports Syndrome Pp

04/12/23 Dr. Abrar Ali Katpar 1


Alport SyndromeDr. Abrar Ali Katpar

Resident Nephrology/MedicineKing Khalid Hospital

Hail, KSA


INTRODUCTION


Background

In 1927, Cecil A. Alport described 3 generations of a family with combinations of progressive hereditary nephritis & deafness.

Alport also noted that hematuria was the most common presenting symptom, & that males were affected more severely than females.

Subsequently, many more families were described, & the eponym Alport syndrome (AS) was coined in 1961.


DISEASE TREND

In most patients, – Disease is inherited as :- – X-linked trait

however, some families have – Autosomal recessive &– Autosomal dominant forms.


Pathophysiology


Pathophysiology

The GBM is a sheetlike structure between the capillary endothelial cells and the visceral epithelial cells of the renal glomerulus.


Pathophysiology

Type IV collagen is the major constituent of the GBM.


Type IV collagen molecule

Composed of 3 subunits– Called alpha (IV) chains– Chains are intertwined into a triple helical

structure. – 2 molecules at C- terminal.– 4 molecules at N- terminal.– Forms a “chicken wire” network.

6 isomers Alpha-1(IV) to Alpha-6(IV).


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

Alpha (IV) Chain

Genes ChromosomalLocation

Mutation

Alpha-1 (IV) COL4A1 13 Unknown

Alpha-2 (IV) COL4A2 13 Unknown

Alpha-3 (IV) COL4A3 2 ARAS*

Alpha-4 (IV) COL4A4 2 ARAS

Alpha-5 (IV) COL4A5 x XLAS†

Alpha-6 (IV) COL4A6 x Leiomyomatosis‡

* Autosomal recessive AS (mutations spanning 5' regions of COL4A5 and COL4A6 genes)† X-linked AS‡ Autosomal recessive AS


Pathophysiology

The alpha-1 (IV) and alpha-2 (IV) chains are ubiquitous in all basement membranes

But the other type IV collagen chains have more restricted tissue distribution.


Tissue Distribution of Alpha (IV) ChainsAlpha (IV) Chain

Tissue Distribution

Alpha-1 (IV) Ubiquitous

Alpha-2 (IV) Ubiquitous

Alpha-3 (IV) GBM, distal TBM*, Descemet membrane, Bruch membrane,

anterior lens capsule, lungs, cochlea

Alpha-4 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane,


Alpha-5 (IV) GBM, distal TBM, Descemet membrane, Bruch membrane,


Alpha-6 (IV) Distal TBM, epidermal basement membrane * Tubular basement membrane


Pathophysiology

Frequency ratio of AS is 1:5000. Three genetic forms of AS exist:

I. XLAS, • which results from mutations in the COL4A5 gene and

accounts for 85% of cases;

II. ARAS, • which is caused by mutations in either the COL4A3 or the

COL4A4 gene and is responsible for approximately 10-15% of cases.

III. 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.


Pathophysiology

In the COL4A5 genes from the families with XLAS, – > 300 gene mutations have been reported.

Most COL4A5 mutations are small – ie, <10–base pair [bp]– Include :-

• Missense mutations, • Splice-site mutations, • Small deletions.


Pathophysiology

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.


Pathophysiology

In 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.

Pt’s are either homozygous or compound heterozygous for their mutations, and their parents are asymptomatic carriers.


Pathophysiology

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.


PathophysiologyPathogenesis of renal failure remains poorly

understood in AS. The primary abnormality results from

aberration of basement membrane expression of alpha-3,4,5 (IV) chains of type IV collagen.

These chains are usually underexpressed or absent from the basement membranes of patients with AS.


PathophysiologyThe 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.


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


Pathophysiology

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-3,4,5 (IV) chains are thought to enhance the resistance of GBM to proteolytic degradation at the site of glomerular filtration.

Persisting of alpha-1, 2 (IV) isoforms confers an unexpected increase in susceptibility to proteolytic enzymes, leading to basement membrane splitting and damage.


Pathophysiology Evidence now suggests that :-

– Accumulation of types V and VI collagen chains in the GBM occurs as a compensatory response to the loss of alpha-3,4 & 5 (IV) chains.

Types V and VI collagen chains 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.


Frequency

In the US– AS is accounts for approximately 3% of children

and 0.2% of adults with ESRD.

Internationally – In Europe, AS accounts for 0.6% of patients with

ESRD.


Mortality / Morbidity

AS is a progressive disease leading 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.

– Approx. 90% pt’s. develop ESRD by 40 y.

– Approx. 75% of pt’s. < 30 years develop ESRD • ie, juvenile type.



Renal prognosis depends on the kind of mutation. The probability of ESRD in < 30 years

– Large rearrangement of the COL4A5 gene • 90% chances

– Minor mutations • 50 - 70% chances

The rate of progression of renal disease is fairly constant in a particular family but variable 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 :-

– Episodes of gross hematuria in childhood,

– Nephrotic range proteinuria,

– Diffuse GBM thickening visible with electron microscope.


Sex

In patients with XLAS, • Severe in males.• 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 not hematuria in first decade of life, unlikely to

have AS. Proteinuria absent in childhood

– But later may develop in males with XLAS and in both males and females with ARAS.

Hearing loss and ocular abnormalities are never present at birth.– Usually become apparent by late childhood or early

adolescence. – Generally before the onset of renal failure.


CLINICAL


History

XLAS = disease severe in males and is much less symptomatic in females. – Clinical features are best described in patients

with XLAS.ARAS = the disease is equally severe in

male and female homozygotes. Carriers (heterozygotes) of ARAS = Mild

clinical manifestations are observed.


Renal manifestations

Hematuria – Gross or microscopic hematuria is the most

common and earliest manifestation of AS.

– Microscopic hematuria is observed • In all males.• In 95% females.

– Persistent in males.

– Intermittent in females.



Hematuria – Like immunoglobulin A (IgA) nephropathy,

60 - 70% of pt’s experience episodes of gross hematuria, often precipitated by upper respiratory infection, during the first 2 decades of life.



Proteinuria – Proteinuria is usually absent in childhood– Later develops in males with XLAS &

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 both 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, with AS.

Some families with AS have severe nephropathy but normal hearing.


Ocular manifestations

Anterior lenticonus – This condition occurs in 25% of pt’s with

XLAS.

– Not present at birth, but it worsens with age.

– It is pathognomonic feature of AS and manifests by a slowly progressive deterioration of vision, requiring patients to change the prescription of their glasses frequently.



–Not accompanied by • Eye pain.

• Eye redness.

• 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.

– Some patients may develop slowly progressive visual impairment.


Leiomyomatosis– Diffuse leiomyomatosis of the esophagus and

tracheobronchial tree has been reported in some families.– Confirmed by CT scan or MRI. – Symptoms usually appear in late childhood :-

• Dysphagia.• Postprandial vomiting. • Substernal pain.• Epigastric pain. • Recurrent bronchitis. • Dyspnea.• Cough. • Stridor.


ARAS – ARAS is much less common than XLAS,

• Usually 10-15% of all patients with AS.

• Usually in consanguineous marriages.

– The parents are asymptomatic or mildly affected, • Their children equally & severely affected.

– The clinical features usually identical to those pt’s with XLAS.

– Renal failure may have an earlier onset in ARAS. – Dot-and-fleck retinopathy and anterior lenticonus

also occurs in ARAS.


ADAS– It is rare.

– Present in successive generations.

– Both sex equally & 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.


ADAS– Clinical features confined to ADAS include

• Bleeding tendency, • Macrothrombocytopenia. • Abnormalities of platelet aggregation

– Epstein syndrome

– Occasionally.• Neutrophil inclusions that resemble Dohle bodies

e.g;– May-Hegglin anomaly, – Fechner syndrome.


Physical Examination


Physical Examination

Initially, the findings on physical examination may be unremarkable.

Patients develop progressive renal failure manifested by – Hypertension. – Edema. and – Anemia.


Extra-renal features1. 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.


Extrarenal features

–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.


Extrarenal features– Approximately 60% of patients with ARAS

usually develop hearing loss when they are younger than 20 years.

– Studies of brainstem auditory-evoked responses indicate the cochlea as the site of the lesion.

– Striking alterations of the stria vascularis of the cochlea is described.


Extrarenal features

2. 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.


Extrarenal featuresAnterior lenticonus

–This condition is not present at birth but worsens with age.

–Anterior lenticonus is the • Pathognomonic feature • Valuable marker of disease severity • Accompanied by progressive renal

failure • Hearing loss.


Extrarenal features Anterior lenticonus

• Dx, is made by slit lamp exam.

• Minor degrees of lenticonus are difficult to detect.

• Dx, is confirmed when the central part of the lens projects anteriorly 3-4 mm in an axial projection on biomicroscopic examination.


Extrarenal features Anterior lenticonus

• The condition is usually bilateral– Causes a slowly progressive axial myopia.

– Rarely may progress to anterior capsular cataract.

– Surgical extraction is treatment.

• This condition rarely progresses to spontaneous rupture of the lens capsule, and posterior lenticonus is very uncommon.


Extrarenal features

– Dot-and-fleck retinopathy• Most common ocular manifestation.• Approximately 85% of males with XLAS. • This 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.


Extrarenal featuresDot-and-fleck retinopathy

• No visual impairment or night blindness occurs.

• 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.


Extrarenal features– Posterior polymorphous corneal dystrophy

• It is rare ocular manifestation.

• Clear vesicles alone or in groups (string of pearls) on the endothelial surface of the cornea.

• It is attributed to the lamellation and thickening of the outer layer of the Descemet membrane.

• It’s demonstration in any individual is highly suggestive of AS.


Extrarenal features

– 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.


Extrarenal features

• 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

– 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.


D DOther Problems to be Considered

IgA Nephropathy

Thin GBM disease


Lab StudiesUrinalysis

– Urinary dipstick test• Hematuria and

• Proteinuria.

– 24-hour urine specimen for • Protein and

• Creatinine.

– Urinary sediment by microscope • To detect dysmorphic RBC’s & RBC casts.


Lab Studies

Hematuria– Urinary sediment frequently reveals

dysmorphic RBC’s and RBC casts. – Whenever possible, screening of the first-

degree relatives for microscopic hematuria of glomerular origin should be performed.


Lab Studies

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, it shows healthy-sized

kidneys.

– With advancing renal failure, the kidneys become smaller and echogenic.


Other Tests

Genetic analysis– Screening for genetic mutations may be

considered in doubtful diagnosis• The screening for COL4A3, COL4A4, and COL4A5

mutations is – Expensive. – Time consuming, – Extremely difficult, and – Not widely available.

– The current detection rate of COL4A5 mutations in relatives with AS is 50%.


Procedures

Biopsy – Obtain tissue from the kidneys and skin to

reveal ultrastructural abnormalities.• Skin biopsy is less invasive should be

obtained first.• Kidney biopsy most often provides the

diagnosis if it is not established by skin biopsy.


Histologic Findings

– Absence of alpha-5 (IV) chains of type IV collagen in the epidermal basement membrane on skin biopsy is diagnostic of XLAS.

– It is observed in only 80% of males with XLAS.

– In such cases, kidney biopsy is not necessary for diagnosis.


Histologic Findings

– Presence of alpha-5 (IV) chains in the epidermal basement membrane does not rule out the diagnosis of XLAS.

– The alpha-5 (IV) chain is expressed in the epidermal basement membrane in autosomal recessive disease.

– 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.


Electron micrograph of kidney biopsy from a patient with Alport syndrome (AS).

Note the splitting and lamellation of the glomerular basement membrane


Alport syndrome


Histologic Findings

– 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.


Histologic Findings

– 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.

– Renal expression of type IV collagen alpha-3 (IV), alpha-4 (IV), and alpha-5 (IV) chains can differentiate XLAS and ARAS.


Histologic Findings

– 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;

– 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.


Histologic Findings

– Electron microscopy reveals diffuse thickening and splitting of the basement membrane in 60-90% of patients.

– Diffuse thinning in rest of the numbers.


TREATMENT


Medical Care

– No definite treatment exists for AS. – 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.

– Gene therapy UNDER study.


Surgical Care

– Renal transplantation is usually offered to patients with AS who develop ESRD.

– The allograft survival rate in these patients is similar to other renal diseases.

– Recurrent disease does not occur in the transplant.– 3-5% of patients develop anti-GBM nephritis. – Excellent graft survival rates – Very low incidence of anti-GBM disease.


Consultations

Ophthalmologist Otorhinolaryngologist Transplant surgeon Surgeon Dialysis specialist


Diet

Patients require a renal failure diet once ESRD ensues.


MEDICATION


Treatment

ACE inhibitors

orAngiotensin-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. • 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 Name Enalapril (Vasotec) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.

Adult Dose 5 mg/d PO initial; not to exceed 40 mg/d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; angioedema

Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics

Pregnancy D - Unsafe in pregnancy

PrecautionsCategory D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; monitor serum potassium


Drug Name Fosinopril (Monopril) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.


Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; collagen vascular disease; angioedema

Interactions

NSAIDs may reduce hypotensive effects of fosinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases fosinopril levels; probenecid may increase fosinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics




Drug Name Lisinopril (Zestril, Prinivil) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.


Pediatric Dose

Not established

Contraindications


Interactions

NSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics




Drug Name Quinapril (Accupril) -- Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.


Pediatric Dose

Not established

Contraindications


Interactions

NSAIDs may reduce hypotensive effects of enalapril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases enalapril levels; probenecid may increase enalapril levels; the hypotensive effects of ACE inhibitors may be enhanced when administered concurrently with diuretics




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.


Drug Name

Losartan (Cozaar) -- Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors and do not affect the response to bradykinin and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.


Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

InteractionsKetoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of losartan

Pregnancy C - Safety for use during pregnancy has not been established.



Drug Name

Candesartan (Atacand) -- Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors and do not affect the response to bradykinin and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.


Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

InteractionsKetoconazole, sulfaphenazole, and phenobarbital may decrease effects; cimetidine may increase effects of candesartan

Pregnancy C - Safety for use during pregnancy has not been established.

PrecautionsCategory D in second and third trimester of pregnancy; caution in renal impairment (serum creatinine >3.5), valvular stenosis, or severe congestive heart failure; watch for serum potassium


Further Outpatient Care

– Control the patient's blood pressure.– ACE inhibitors or ARB’s to control proteinuria.– Monitor renal function test results and proteinuria.– Check 24-hour urinary protein, creatinine, and

serum chemistry • On an annual basis in patients without renal insufficiency

or

• Those with mild renal insufficiency.

• Every 6 months in moderate renal insufficiency.

• Every 1-3 months in 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 in 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.


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.

– Certain patients are at very low risk for developing posttransplant anti-GBM nephritis.


– 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.


THANKS


MEANING EPONYM

– The name of a disease, structure, operation, or procedure, usually derived from the name of the person who discovered or described it first.

COINED– The word 'psychiatry' was coined to refer to the institution of a discipline within

medicine.


Collagen The major protein of the white fibers of

– connective tissue, – cartilage, and – bone, that is insoluble in water but can be altered to easily digestible, soluble

gelatins by boiling in water, dilute acids, or alkalies. It is high in glycine, L-alanine, L-proline, and L-4-

hydroxyproline, but is low in sulfur and has no L-tryptophan. Collagen comprises a family of genetically distinct molecules all

of which have a unique triple helix configuration of three polypeptide subunits known as )-chains;

11 types of collagen have been identified, each with a different polypeptide chain.

– Also: collagen fiber. – Syn: ossein, osseine, ostein, osteine.

Alports Syndrome Pp

Health & Medicine

Transcript of Alports Syndrome Pp