Alport syndrome

Alport syndrome – 13 Interesting Facts

AS (Alport syndrome) is a genetic degenerative kidney disorder characterized by glomerular kidney disease caused by abnormal collagen IV (ie, type IV collagen) resulting in fragile glomerular basement membrane
Pathogenic variants of COL4A3, COL4A4, or COL4A5 lead to abnormalities in structure and function of collagen IV
Condition is associated with a spectrum of clinical phenotypes ranging from isolated hematuria to progressive kidney disease and kidney failure¹
Sensorineural hearing loss and eye abnormalities are frequent associations
Disease displays varying inheritance depending on the gene affected: X-linked (about 65% of disease), autosomal recessive (15%), or autosomal dominant (20%)
AS is often underdiagnosed or misdiagnosed as other kidney disorders, particularly in patients with atypical or mild symptoms⁵
Suspect disease based on clinical presentation that often involves positive family history of kidney disease along with unexplained, persistent microscopic hematuria with or without associated proteinuria
Genetic basis for diagnosis is typically confirmed by identification of COL4A3, COL4A4, or COL4A5 pathologic variant responsible for disease
Approach to treatment may vary depending on specific disease manifestations, degree of proteinuria, severity of kidney dysfunction, age of patient, and AS genotype
General goals of treatment include prevention of rapidly progressive kidney dysfunction and monitoring for development and management of complications (eg, chronic kidney disease, ocular conditions associated with AS, midrange sensorineural hearing loss)
Early initiation of ACE inhibitor or angiotensin receptor blocker is associated with slower progression of glomerular disease
AS often leads to progressive kidney damage over time, and individual prognosis tends to vary depending on several factors (eg, specific genetic variant, age at onset of proteinuria, presence of complications, adequacy of medical management)
The rate of progression can vary widely among individuals. Some may experience a slower decline in kidney function, whereas others’ condition may progress more rapidly

Alarm Signs and Symptoms

Development of proteinuria in a patient with AS signals need to initiate ACE inhibitor or angiotensin receptor blocker in effort to slow progressive kidney damage

Introduction

AS (Alport syndrome) is a genetic degenerative kidney disorder characterized by glomerular kidney disease caused by abnormal collagen IV (ie, type IV collagen) resulting in fragile GBM (glomerular basement membrane)
Collagen IV
- Type of collagen found in the mature GBM and the mature basement membranes throughout the eye and cochlea
- It is composed of 3 interwoven chains from the group of α1-6(IV), encoded by 6 different genes (COL4A1–COL4A6)
- In fetal life the α1,1,2(IV) heterotrimer is the predominant form of collagen IV and is subsequently replaced by the stronger α3,4,5(IV) network
- AS is caused by pathogenic variants in COL4A3, encoding α3(IV); COL4A4, encoding α4(IV); or COL4A5, encoding α5(IV)
Persistent hematuria²
- Persistent hematuria is defined as RBC count in urine more than 20 × 10⁶ cells/µL for 6 months or longer
Urinary markers of renal insufficiency
- Urinary loss of protein indicates glomerular damage and is a marker for progression of kidney disease; detection of urinary proteinuria guides therapeutic approach
- Albuminuria³
  - Measurement of albuminuria is gold standard to quantify urinary protein since albumin is the most prevalent protein found in the urine in many forms of proteinuric kidney disease
  - First morning sample measuring urinary albumin to creatinine ratio (urinary ACR) quantifies protein loss and guides the commencement of therapy in multiple Alport syndrome guidelines
- Proteinuria²
  - Urinary protein to creatinine ratio (urinary PCR) is an acceptable alternative to urinary ACR when that ratio is not readily available
Condition is associated with a spectrum of clinical phenotypes ranging from isolated hematuria to progressive kidney insufficiency¹
Hearing loss and eye abnormalities are frequent associations
May be named according to the gene affected, the mode of inheritance, or the effect on the kidney (eg, X-linked AS, COL4A5 glomerulopathy)

Background Information

Course of disease is variable
- Patients with AS are born with normal kidney function
- Accumulation of abnormal collagen IV leads to an increasingly fragile GBM and hematuria then develops
- With time, depending on the severity of the genetic variant, proteinuria may follow, heralding progressive decline in kidney function
- Eventually, CKD (chronic kidney disease) and kidney failure may result
In the past, patients with heterozygous variants in COL4A3 or COL4A4 may have been classified as having thin basement membrane disease based on kidney biopsy or benign familial hematuria based on family history⁴⁵⁶⁷
- Both descriptions reflect the impression that most individuals experience a mild phenotype limited to hematuria
- However, data show that some patients progress to kidney impairment. Up to 19% of some cohorts develop kidney failure, and large-scale genetic testing of cohorts with kidney disease shows that 16% have variants in COL4A3 or COL4A4
Therefore, use of the term autosomal dominant Alport syndrome rather than either thin basement membrane disease or benign familial hematuria for cases of pathogenic heterozygous variants in COL4A3 or COL4A4 is preferred to reflect potential disease impact on health and underscore need for longer-term follow-up

Epidemiology – How common is Alport syndrome?

Prevalence
- AS is a rare genetic disorder
- Prevalence varies among different populations but is estimated to affect approximately 1 in 5,000 to 1 in 10,000 patients⁸
- However, the population frequency of heterozygous pathogenic variants in COL4A3 or COL4A4 is 1 in 106, suggesting that many affected individuals are undiagnosed⁸
Underdiagnosis
- AS is often underdiagnosed or misdiagnosed as other kidney disorders, particularly in patients with atypical or mild symptoms⁵
Sex distribution
- Both sexes may be affected by variants in COL4A3 and COL4A4 equally
- Males with pathogenic variants in COL4A5 have more marked disease severity than females; therefore, the large majority of youth affected by AS are males
Age of onset
- Symptoms typically become noticeable in childhood or early adulthood; however, diagnosis may not be established until later in life, depending on the gene and variant, leading to variations in the age of onset data⁶⁷⁹¹⁰

Etiology – What causes Alport syndrome?

AS is caused by pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes, which encode α3,4,5 chains of collagen IV
- Collagen IV is a crucial component of the mature GBM, as well as the mature basement membranes throughout the eye and cochlea
- Pathologic variants in COL4A3, COL4A4, and COL4A5 lead to abnormalities in structure and function of collagen IV. Result is a weakened basement membrane in kidneys and other affected tissues, making them more predisposed to damage and dysfunction
- At least 1,400 pathologic variants responsible for disease have been identified among the 3 genes responsible for collagen IV¹
Inheritance pattern
- AS displays X-linked, autosomal recessive, or autosomal dominant inheritance, depending on the gene affected¹
  - XLAS (X-linked Alport syndrome): about 65% of disease
  - ARAS (autosomal recessive Alport syndrome): about 15% of disease
  - ADAS (autosomal dominant Alport syndrome): about 20% of disease
- Inheritance pattern estimates are likely to vary over the next few years as more patients with ADAS receive genetic diagnoses, since 1 in 106 of some populations have a single pathogenic or likely pathogenic variant in COL4A3 or COL4A4⁸
- Variants in COL4A3 and COL4A4 can be inherited in a dominant or recessive pattern, whereas variants in COL4A5 are inherited in an X-linked pattern
- Digenic inheritance (ie, disease secondary to presence of 2 different pathologic variants responsible for disease among COL4A3, COL4A4, and COL4A5) has been demonstrated in few patients with AS¹
- Spontaneous de novo pathologic variants responsible for disease are reported
OMIM entries for AS include the following:
- Alport syndrome autosomal dominant pathologic variants of COL4A3 (OMIM *120070)¹¹
- Alport syndrome 3B autosomal recessive pathologic variants of COL4A3 (OMIM #620536)¹²
- Alport syndrome autosomal dominant pathologic variants of COL4A4 (OMIM #141200)¹³
- Alport syndrome autosomal recessive pathologic variants of COL4A4 (OMIM #203780)¹⁴
- Alport syndrome X-linked pathologic variants of COL4A5 (OMIM #301050)¹⁵
Genotype-phenotype correlations
- High degree of inter- and intrafamilial phenotypic variability is noted among patients with AS, particularly among females with XLAS¹⁶¹⁷
- Truncating variants in COL4A5 are associated with more severe disease in males with XLAS. Impact of specific variants on kidney function decline is yet to be fully elucidated given the numerous pathologic variants responsible for disease known among the 6 genes that encode α chains for collagen IV¹⁷¹⁸
- Some generalizations are anticipated as follows:
  - Males with XLAS develop progressive CKD¹⁰¹⁶¹⁷¹⁹²⁰
    - Patients with COL4A5 variants where the α3,4,5(IV) network is absent (eg, truncating variants, nonsense variants, large deletions) have a median age at kidney failure of 29 years
    - Patients with COL4A5 variants with some degree of expression of the α3,4,5(IV) network (eg, missense variants) are associated with slower progression of kidney disease with kidney failure in early adulthood during the 30s or 40s
  - Females with XLAS⁹¹⁶
    - Often have hematuria, with a minority progressing to kidney failure in late adulthood. Genotype-phenotype correlations are not established in this group but are likely to follow those of males with XLAS

What are the Risk Factors?

Risk factors for Alport syndrome include:
- Positive family history of AS, thin basement membrane disease, or benign familial hematuria
Risk for progression of kidney disease is variable and dependent on several factors
- Sex
  - Males with XLAS generally experience more severe kidney disease progression compared with females²¹²²
- Age of onset
  - Those with early age of onset of symptoms (eg, hematuria) may be at greater risk of rapid kidney disease progression; early initiation of treatment may minimize risk
- Family history
  - Positive family history of AS with kidney failure or severe kidney disease may be associated with increased risk of progression
- Hypertension
  - Uncontrolled high blood pressure can accelerate kidney damage in AS; risk is minimized with effective management of hypertension
- Proteinuria
  - Proteinuria is a marker of kidney dysfunction in AS, and higher levels of proteinuria may indicate more advanced kidney disease with greater risk of progression
- Regular monitoring
  - Lack of regular kidney function test monitoring (eg, serum creatinine level, eGFR [estimated glomerular filtration rate]) may limit early identification of disease progression and be a missed opportunity to guide appropriate interventions

Diagnosis

Approach to Diagnosis

Suspect disease based on clinical presentation
- Maintain awareness that Alport syndrome is often underdiagnosed or misdiagnosed as other kidney disorders, particularly in cases with atypical or mild symptoms⁵
Assess baseline urinalysis results (hematuria and albuminuria/proteinuria) and basic kidney function test results (eg, creatinine level, eGFR calculation)
- Hematuria and proteinuria are common early signs of AS
Diagnosis is typically confirmed with genetic testing by identification of COL4A3, COL4A4, or COL4A5 pathologic variant responsible for disease
Kidney biopsy, and in select circumstances skin biopsy, may be performed if diagnosis remains uncertain after genetic testing
- Kidney biopsy results typically exhibit characteristic changes in the GBM; however, because AS is a progressive condition, the characteristic features may not be evident early in the course of the disease (eg, in childhood)
Collaborative approach involving diagnostic team (eg, nephrologists, geneticists, genetic counselors) is crucial for timely and accurate diagnosis
Postdiagnostic investigation includes the following:
- Baseline kidney ultrasonography
  - Indicated to assess kidney structure and size and to evaluate for unrelated structural anomalies of the kidneys that could affect disease progression
- Audiologic assessment
  - Obtain formal audiologic evaluation with audiometry and tympanometry to evaluate for hearing deficits
- Ophthalmologic evaluation
  - Refer to ophthalmologist for examination to assess for visual deficits and common associated eye abnormalities²³

Workup

History

Unexplained persistent microscopic hematuria and/or proteinuria is a common presenting pattern
- Microscopic hematuria is the most common initial manifestation of Alport syndrome, occurring in more than 95% of males and females with XLAS and at least 60% of those with ADAS²⁴²⁵
- Hematuria is usually persistent; consider AS with persistent hematuria more than 6 months in duration
- Macroscopic hematuria can occur at times of infection or inflammation
- Proteinuria develops with worsening glomerular disease; frothy urine may signal presence of proteinuria
Personal history may reveal visual and hearing abnormalities frequently associated with AS
- Loss of vision and previous diagnosis of ocular abnormalities associated with AS (eg, keratoconus, dot-and-fleck retinopathy, temporal macular thinning, early-onset cataract formation, retinal detachment)
- Symmetrical and progressive sensorineural hearing loss, particularly in the midfrequency range
Family history may reveal history of kidney disease, hearing loss, and eye problems
Symptoms of kidney impairment (fatigue, edema, nausea, anorexia) may be noted

Physical Examination

Most commonly the physical examination findings are unremarkable
Hypertension may signify kidney impairment
Signs of kidney impairment may be noted, such as edema
Ophthalmologic examination may reveal ocular abnormalities associated with Alport syndrome (eg, keratoconus, dot-and-fleck retinopathy, temporal macular thinning, early-onset cataract formation, retinal detachment)
Audiologic assessment may reveal symmetrical mid-frequency hearing loss, also known as “cookie bite hearing loss” (from the shape of the curve)

Laboratory Tests

Urinalysis
- Microscopy of a spot urine sample to quantify RBC count is preferable²
  - Persistent hematuria is defined as RBC count more than 20 × 10⁶ cells/µL for 6 months or longer
  - If such microscopy is not available, then a urine dipstick for hematuria is an acceptable alternative
  - A diagnosis of AS should be considered for all patients with persistent hematuria for 6 months or longer
- A first-morning spot urine sample for urinary ACR is preferable
  - Where that option is not available, a urinary PCR or urine dipstick for proteinuria may be an acceptable alternative. ACR more than 30 mg/g or PCR more than 0.2 mg/mg is abnormal²
  - Measurement of total urinary proteinuria is less specific, and total protein assays are not standardized; however, urinary dipstick is a point of care test and can have a lower cost
Kidney function tests
- Creatinine and eGFR assessments to assess for and determine degree of kidney impairment
Genetic testing
- Identification of a pathogenic or likely pathogenic variant in COL4A3, COL4A4, or COL4A5 associated with disease is diagnostic of Alport syndrome
- Genetic testing of unselected cohorts with kidney disease shows that 16% have variants in COL4A3 or COL4A4, and selected cohorts (eg, children with persistent microscopic hematuria) have a diagnostic yield approaching 50%⁵²⁶²⁷

Imaging Studies

Kidney ultrasonography
- Baseline ultrasonography of kidneys at diagnosis is standard to delineate anatomy (eg, establish presence of 2 normally sized and formed kidneys)²⁸
- Presence of kidney cysts may be consistent with diagnosis²⁸
  - Case reports note presence of kidney cysts in adult patients with ADAS in the absence of separate genetic diagnosis

Diagnostic Procedures

Kidney biopsy
- May be indicated in certain scenarios, including:
  - Genetic testing is unavailable
  - Genetic testing is inconclusive
  - Lack of availability of genetic testing results in a clinically relevant timeframe (eg, patient with nephrotic syndrome where a trial of immunosuppressive therapy is under consideration and could be avoided if genetic results are available in a few weeks)²⁹
- Because Alport syndrome is a progressive condition, its histologic features vary with age, but the following findings on biopsy are highly suggestive of AS:³⁰
  - GBM abnormalities
    - Thinning of GBM
      - Hallmark histologic feature of AS
    - Lamellation of GBM
      - Lamellated or split appearance may be noted and is a characteristic and distinguishing feature of Alport syndrome
    - Basketweave pattern
      - May be described secondary to the splitting of the GBM layers
    - Spiral lamellae
      - May be described within the GBM secondary to irregular folding of GBM
  - Podocyte abnormalities
    - Foot process effacement and detachment from the GBM may be noted among these specialized glomerular cells
  - Interstitial fibrosis and tubular atrophy
    - Represent signs of CKD; may develop with progression of kidney disease in Alport syndrome
  - Focal and segmental glomerulosclerosis
    - Nonspecific changes of this type may be present and may indicate a histologic pattern of injury with many causes of proteinuria (eg, diabetes, hypertension, drug toxicity)
    - Characterized by segmental sclerosis of the glomerulus in a focal distribution (ie, not all glomeruli are affected)
Skin biopsy
- Occasionally used by a small number of centers in diagnostic process to evaluate for XLAS
  - Immunostaining for collagen α5(IV) is used to assess for XLAS³¹
  - Method cannot be used to assess for ARAS or ADAS because neither α3(IV) nor α4(IV) is present in the skin
- May be indicated in certain clinical scenarios (eg, when a patient is not a suitable candidate for a kidney biopsy and genetic testing results are not available)
- After incubation of the skin tissue with a monoclonal antibody against α5(IV), a positive result shows no staining³²

Differential Diagnosis

Alport syndrome includes hereditary glomerulonephritis and deafness.
Up to 85% patients have mutations in X chromosome COL4A5 gene, while 15% are AR with defects in COL4A3 or COL4A4 genes.
The defect is in a nonfibrillar basement membrane collagen (type IV collagen), which is an important component of the kidney basement membrane.
Patients present with hematuria, sensorineural hearing loss, fleck retinopathy, and lenticonus.
They can progress to renal failure.

Table 1. Differential Diagnosis: Persistent microscopic hematuria for longer than 6 months.

Condition	Description	Differentiated by
IgA nephropathy	• Most common form of glomerulonephritis; overall population incidence is 2.5/100,000³³ • Glomerulonephritis presenting with synpharyngitic macroscopic hematuria ± proteinuria during episodes of infection, most commonly of the upper respiratory tract³⁴ • Outcomes vary depending on presentation; among those who progress to a kidney biopsy (eg, because of kidney impairment or significant proteinuria), most will progress to kidney failure within 10-15 years³⁵	• Characteristic pattern of disease typically differentiates • Diagnosis may be confirmed by kidney biopsy, when indicated (eg, if kidney impairment or significant proteinuria)
Postinfectious glomerulonephritis	• Relatively common childhood condition • Typically presents about 2 weeks after a streptococcal infection (such as a sore throat or impetigo) with macroscopic hematuria ± proteinuria³⁶ • Associated with a transient change in serum complement levels (decreased C3 and normal or mildly decreased C4)³⁶	• Clinical diagnosis based on characteristic pattern of disease • Decreased C3 differentiates from Alport syndrome • Diagnosis may be confirmed by kidney biopsy, when indicated (eg, if kidney impairment or significant proteinuria)³⁷
Hemolytic uremic syndrome	• Multisystem disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney impairment • Often hemolytic uremic syndrome is triggered by infection with Shiga toxin–producing Escherichia coli or Streptococcus pneumoniae (typical form) or caused by chronic uncontrolled activation of the complement system (atypical form)³⁸³⁹⁴⁰	• Differentiated from Alport syndrome by characteristic pattern of disease; in particular, thrombocytopenia is not a feature of Alport syndrome
IgA vasculitis (Henoch-Schönlein purpura)	• Most common childhood vasculitis. Incidence is 20/100,000 children/year, with 90% of patients younger than 10 years⁴¹⁴² • Condition is characterized by palpable purpura, typically on buttocks and lower limbs. It may be associated with abdominal pain, arthritis, and glomerulonephritis	• Differentiated from Alport syndrome by characteristic pattern of disease; in particular, palpable purpuric rash is not a feature of Alport syndrome • Generally a clinical diagnosis that may be confirmed by kidney biopsy, when indicated (eg, if kidney impairment or significant proteinuria)
Systemic lupus erythematosus	• Chronic multisystem autoimmune disease that can be diagnosed using the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria with 96% sensitivity⁴³ • Most patients are female; 40% develop glomerulonephritis⁴⁴	• Differentiated from Alport syndrome by multisystem disease • Diagnosis is usually established by a combination of clinical manifestations and serologies (eg, negative result for ANA [antinuclear antibodies] strongly suggests against this disease). Kidney biopsy may be required for disease staging and to guide therapeutic decisions when patient presents with glomerulonephritis⁴³
Kidney stones	• May present similarly with persistent hematuria • Usually associated with flank and groin pain	• Suspect diagnosis by clinical presentation • Confirm diagnosis by imaging, typically ultrasonography or CT
Blood loss from bladder	• Can present similarly with microscopic hematuria; however, gross hematuria is most characteristic • Various underlying causes may include malignancy (eg, renal cell carcinoma, bladder cancer, prostate cancer), urethral stricture, prostatitis, prostate hyperplasia, urethritis, and cystitis	• Microscopy may reveal nonglomerular blood cells • Differentiated from Alport syndrome by presence of bleeding on cystoscopy
Genetic glomerulopathies	• May present similarly with microscopic hematuria • Genetic causes include pathogenic variants in COL4A1, which is associated with angiopathy, and MYH9, which is associated with macrothrombocytopenia and granulocyte inclusions⁴⁵⁴⁶	• Eye findings, sensorineural hearing loss, and classical family history consistent with AS are absent • Differentiate with genetic testing. Specific list of genes and potential pathologic variants of interest is maintained by PanelApp⁴⁶ • Biopsy may be considered in select patients, particularly with significant proteinuria where a diagnostic trial is under consideration

Treatment

Approach to Treatment

A team approach that includes a nephrologist and a genetic counselor is recommended for optimal management
General goals of treatment involve:
- Slow the decline of kidney function
- Monitor for development and management of complications
- Prepare for transplant if required
Approach to treatment may vary depending on specific disease manifestations, degree of proteinuria, severity of kidney dysfunction, age of patient, and AS genotype
Prevention of proteinuria and kidney function decline
- RAAS (renin-angiotensin-aldosterone system) blockade
  - Primary treatment strategy involves pharmacologic RAAS blockade with ACE inhibitors (blocking angiotensin-converting enzyme activity) or ARBs (angiotensin receptor blockers) to reduce intraglomerular pressure and diminish proteinuria²¹²²⁴⁷
    - ACE inhibitors are first line and ramipril is initial drug of choice⁴⁸
  - Indications for initiation of RAAS blockade include:⁴⁸⁴⁹
    - In patients aged 2 years or older: males with XLAS and anyone with ARAS
    - Onset of microalbuminuria (ie, first morning spot urine ACR more than 30 mg/g) in females with XLAS and in anyone with ADAS
  - RAAS blockade has been demonstrated to be safe and effective in delaying the progression of disease and is more efficacious the earlier it is started (ie, the younger the better)
    - Historical cohort data demonstrate the following when comparing stage at which treatment with RAAS inhibition is started to the age of onset of kidney failure:⁵⁰⁵¹
      - Patients starting RAAS inhibition in established CKD experience kidney failure at a median age of 25 years, compared with 22 years when no treatment is initiated
      - Patients starting RAAS inhibition at the onset of proteinuria experience kidney failure at a median age of 40 years
      - None beginning treatment with isolated hematuria display evidence of kidney failure after 20 years of follow-up
    - Evidence shows that control of proteinuria is associated with a significant slowing of disease progression. EARLY PROTECT trial supports the safety and efficacy of ramipril for children aged 2 years or older with AS for reducing rate of progression of proteinuria⁴⁸⁵²
  - Despite aggressive treatment with RAAS blockade, lifetime risk of kidney failure is high among most people with AS
    - Males with XLAS and patients with ARAS often progress to kidney failure in early adulthood
- SGLT2 inhibitors (blocking sodium-glucose cotransporter 2 activity)
  - Extensive evidence exists supporting the use of SGLT2 inhibitors to slow progression of kidney disease of all causes, including in patients with AS, and these drugs are approved for use in patients with nondiabetic CKD at risk of progressing to kidney failure⁵³⁵⁴⁵⁵
  - These drugs, through various mechanisms, lead to reduced intraglomerular pressure, thereby reducing proteinuria⁵⁶
  - Reduction in proteinuria over a mean of 21 months of treatment is associated with use of SGLT2 inhibitors in adults with Alport syndrome and early CKD⁵⁷
  - Evidence of safety and efficacy in adults with AS who have CKD is accumulating
Management of complications
- Hypertension
  - Recommend lifestyle modifications as outlined in established guidelines (eg, reduce dietary salt intake, consume a healthy diet, pursue weight reduction and smoking cessation, maintain regular physical activity)⁵⁸⁵⁹
  - First line options for blood pressure control include ACE inhibitors or ARBs
  - Second line treatments are based on local and regional blood pressure guidelines for patients with CKD⁵⁸⁵⁹

Drug Therapy

ACE inhibitors
- First line for control of proteinuria with dosing as per local blood pressure guidelines⁵⁸⁵⁹
- Contraindications include pregnancy
- Long-acting agents for once daily dosing are preferred. Ramipril is specific agent most studied in prevailing clinical trials, and used most clinically with greatest safety record among patients with Alport syndrome⁵²⁶⁰
- Ramipril is initial drug of choice⁴⁸
  - Adults: initial dose 2.5 mg PO once a day. Adjust dose as tolerated to a maximum of 20 mg/day according to blood pressure response, aiming to avoid postural hypotension while minimizing proteinuria⁶¹
  - Children: initial dose for children is 1.6 mg/m²/day PO. Increase dose as tolerated to a maximum of 6 mg/m²/day, aiming to avoid postural hypotension while minimizing proteinuria⁵⁹
ARBs
- For control of proteinuria with dosing as per established blood pressure guidelines⁵⁸⁵⁹
- Contraindications include pregnancy
- Irbesartan
  - Recommended as possible add-on therapy⁴⁸
  - Adults: initial dose for adults is 150 mg PO once daily. Adjust dose as tolerated to a maximum of 300 mg/day according to blood pressure response, aiming to avoid postural hypotension while minimizing proteinuria⁶²
  - Children: initial dose for children aged 6 to 12 years is 75 mg/day PO increasing to 150 mg/day, according to blood pressure response, aiming to avoid postural hypotension while minimizing proteinuria. Dose as per adults from age 13 years onward⁵⁹⁶³

Nondrug and Supportive Care

Anticipatory guidance and education⁶⁴
- Recommend smoking avoidance or cessation to reduce the risk of kidney disease progression
- Although individuals with Alport syndrome are not more predisposed to urinary tract infections than the general population, promptly treat any such infections that may occur, and consider prevention measures such as encouraging increased fluid intake, regular voiding, estrogens, cranberries, prophylactic antibiotics, or probiotics⁶⁵
- Avoid nephrotoxic substances and review medication choices with pharmacist
- Maintain a balanced diet and proper hydration to support kidney health and slow the progression of kidney disease; patients with established CKD may benefit from dietary review with a specialist renal dietitian
- Encourage regular exercise
- Discuss kidney replacement therapy options and donor selection in early CKD⁶⁶
- Monitor blood pressure measurement under the guidance of a nephrologist or other health care practitioner specializing in kidney disease
- Monitoring kidney function with kidney function tests (eg, serum creatinine level, eGFR calculation) and urinalysis (spot ACR or PCR)
- Recommend routine audiologic and ophthalmologic examinations
- Provide patient resources; some available resources include:
  - Adult treatment overview⁶⁷
  - Pediatric treatment overview⁶⁸
  - AS family planning guide⁶⁹
- Inform patients of any clinical trials that they may be eligible for; consider enrollment on an individualized basis, with shared decision-making among patient, family, and health care practitioners
Genetic counseling
- Offer all patients genetic counseling regarding genetic sequencing, interpretation of results, recommendations to support informed reproductive decision-making, and support cascade or family testing
- Offer to first-degree relatives (eg, siblings, parents) of patients with AS to help identify at-risk family members who may consider genetic testing when familial pathologic variants responsible for disease are known

Treatment Procedures

KRT (kidney replacement therapy)⁶⁶
- Includes hemodialysis, peritoneal dialysis, and kidney transplant
- Most suitable option may be determined by patient preference and availability
- Discuss KRT options with the patient and family from CKD stage 3
- Optimal timing of initiation of KRT is an individual decision to be considered from CKD stage 5
- KRT outcomes
  - Dialysis outcomes in patients with AS are comparable with those in patients with other forms of kidney disease and may be superior⁷⁰
  - Kidney transplant outcomes in patients with AS are comparable with those in patients with other forms of kidney disease and may be superior⁷¹
Special considerations for kidney transplant in Alport syndrome
- Potential living-related kidney donors within a family affected by AS may themselves be affected by AS. Parents of patients with ARAS may have ADAS, and siblings of patients with XLAS may themselves have XLAS, albeit less severe
- In general, kidney donation by symptomatic individuals with XLAS or ADAS (eg, hematuria) is not recommended, due to the risk to the donor, though it is not absolutely contraindicated
  - Appropriate workup involves genetic testing and counseling, along with clinical assessment and plans for close monitoring if donation occurs
- Kidney donation by females with XLAS should be an exceptional event, done only after extensive counseling about the increased risk of kidney failure in the donor⁷²⁷³
- Kidney donation by individuals with ADAS carries a lower risk but should be a rare event, done only after extensive counseling
- Patients with severe, early truncating variants in COL4A5 may lack production of any functional α5(IV) collagen and risk development of antibodies targeted at the transplanted kidney
  - Risk of developing anti-GBM antibodies targeted at the transplanted kidney presenting as anti-GBM glomerulonephritis is rare (occurring in around 1%-5% of transplant recipients with Alport syndrome)⁷⁴⁷⁵

Admission Criteria

Standard admission criteria apply for management of kidney impairment

Special Considerations

All Patients With Potential for Pregnancy or Current Pregnancy

FDA has issued a BOXED WARNING against use of ACE inhibitors and ARBs during pregnancy
Discontinuation of ACE inhibitors as soon as possible when pregnancy is detected, plus consideration of alternative treatment, is recommended by most experts to avoid fetal risk; however, continued use may be considered if discontinuing poses a higher risk to the pregnant person⁷⁶⁷⁷⁷⁸
Counsel females of reproductive age that the use of ACE inhibitors or ARBs during pregnancy may be associated with increased risk of fetal harm
- Evidence of increased risk is strongest for second- and third-trimester exposure. Angiotensin blockade may be associated with congenital malformations (eg, oligohydramnios, kidney impairment, patent ductus arteriosus)⁷⁶
- Limited evidence exists that use in the first trimester may increase the risk of malformations⁷⁹⁸⁰
Stress importance of effective contraception to anyone with potential for pregnancy who is taking medications that result in angiotensin blockade, given the risk of fetal harm

Patients With Acute Illness

Provide sick day advice in patients receiving ACE inhibitors or ARBs for proteinuria control rather than blood pressure management
Recommend ceasing temporarily during illness that can result in dehydration (eg, vomiting, diarrhea) and consult health care practitioner
Note that the advice around sick day rules differs when these medications are used for blood pressure control, because cessation may be associated with hypertension⁸¹⁸²

Follow-Up

Monitoring

General routine clinical follow-up
- Frequency of and choice of specific tests recommended at routine follow-up visits vary depending on patient age, stage of kidney disease, medication requirement, and overall health
- Determine frequency of follow-up and specific testing plan in consultation with AS treatment team
Proteinuria monitoring
- The Alport Syndrome Foundation recommends at least annual screening for proteinuria for patients with AS who have yet to develop proteinuria⁶⁴⁸³
CKD monitoring
- Patients with proteinuria require routine monitoring for the development of advancing CKD as outlined by established guidelines⁶⁴
- Frequency of monitoring usually depends on disease severity and on how rapidly the disease is progressing
- Clinical monitoring includes clinical assessment, accurate blood pressure measurement, serum creatinine level, calculated eGFR, serum electrolyte levels, and urinary ACR or PCR and electrolyte levels
Patients requiring RAAS blockade
- Follow-up is recommended at a minimum of every 1 to 2 years for patients receiving prescribed ACE inhibitors and ARBs²³⁶⁴⁸⁴
Audiologic monitoring
- Adults
  - Routine screening for development of hearing deficits is recommended every 1 to 2 years⁸⁴⁸⁵
  - Patients with sensorineural hearing loss should be fitted with bilateral hearing aids with at least annual review
- Children
  - Regular formal hearing evaluation at least every 3 years from age 5 years for children with XLAS or ARAS, or earlier if there are any concerns about hearing⁸⁴⁸⁵
  - Follow more closely in children with minimal threshold elevations (ie, 4PTA between 16 and 25 dB)
  - Patients with sensorineural hearing loss should be fitted with bilateral hearing aids with at least annual review
  - Deficits in language acquisition are reported to be unusual in AS;⁸⁵ however, it is prudent to closely follow language development⁸⁵
Ophthalmologic monitoring
- Regular ophthalmologic assessments to assess general health and to screen for lenticonus should begin at age 11 years for males with XLAS and for anyone with ARAS, or earlier if there are any concerns about vision⁸⁴
  - Routine ophthalmologic monitoring for patients with ADAS is not recommended
- Evaluation by an ophthalmologist is recommended every 1 to 2 years to assess for visual changes or development of eye disease frequently associated with AS⁸⁵
- Assessment includes detailed eye examination and may include retinal photography and retinal optical coherence tomography²³

Complications

CKD and kidney failure
- The frequency of developing kidney failure in AS varies by the gene affected and by the sex of the patient⁷⁰⁷¹⁸⁶⁸⁷⁸⁸
  - XLAS:
    - Males are more severely affected than females
    - 90% of males with XLAS develop kidney failure by age 40 years if untreated
    - 15% to 30% of females with XLAS develop kidney failure by age 60 years
  - ARAS:
    - Males and females are equally affected
    - Majority will develop kidney failure by age 30 years
  - ADAS:
    - Males and females are equally affected
    - Kidney failure typically occurs later in life; one cohort study found median age at kidney failure to be 67 years
Variable associated abnormalities in AS patients may include:
- Ocular abnormalities⁸⁹
  - Anterior lenticonus is a conical deformation of the lens, which leads to progressive worsening of vision
  - Keratoconus
  - Dot-and-fleck retinopathy is a characteristic finding on examination and does not affect vision
  - Posterior polymorphous corneal dystrophy
  - Temporal macular thinning is a condition that may affect visual acuity
  - Early-onset cataract formation
  - Retinal detachment
- Sensorineural hearing loss⁹⁰
  - Pattern of hearing loss in AS is characterized by greater hearing loss in the middle frequencies; therefore, patient may have difficulty hearing some voices or music in midrange
    - Deficits in language acquisition are reported to be unusual in AS⁸⁵
  - Hearing loss is symmetrical and progressive, affecting at least 25% of patients with XLAS⁹⁰
  - Some patients with XLAS exhibit vestibular hypofunction, which is usually not of concern to the patient⁹⁰

Prognosis

Overall prognosis
- AS is a progressive genetic kidney disorder, and individual prognosis tends to vary depending on several factors (eg, specific genetic variant, age at onset of proteinuria, presence of complications, adequacy of medical management)
- Overall prognosis is improved with effective proteinuria management by early initiation of ACE inhibitors and ARBs along with adequate blood pressure control
Progression of kidney disease
- Males with XLAS develop CKD
  - About 60% develop end-stage kidney disease by age 30 years and 90% by age 40 years¹
  - Based on specific pathologic variant for disease¹⁶¹⁷¹⁹²⁰
    - Truncating COL4A5 variants are associated with early-onset kidney failure, whereas nontruncating variants exhibit slower progression of kidney failure
    - COL4A5 variants resulting in absence of α3,4,5(IV) network expression are associated with a rapid progression compared with variants associated with expression of α3,4,5(IV) network
- Females with XLAS have variable disease severity and course
  - Most exhibit isolated hematuria, and a minority progress to renal insufficiency later in adulthood than males with XLAS
  - Variability in outcomes for females is due in part to mutation load and X-inactivation status²¹²²
  - About 12% develop end-stage kidney disease by age 40 years, 30% by age 60 years, and 40% by age 80 years⁹⁴⁷
- ARAS
  - Associated with a relatively rapid course of progression to renal insufficiency
  - Most patients with ARAS develop significant proteinuria as children or adolescents and progress to end-stage kidney disease by age 30 years¹
- ADAS
  - Associated with slower disease course than other forms of AS
  - Most develop progression to end-stage kidney disease only in late adulthood¹
Hearing loss
- Sensorineural hearing loss tends to worsen over time
- Hearing loss may begin in childhood or adolescence and may progress gradually
Ocular disorders and loss of vision
- Patients with XLAS are at highest risk of development of visual impairment and ocular disorders
- Hearing loss and ocular disorders are reported in ARAS and ADAS but much less consistently than in XLAS
- Patients with ADAS are at minimal risk and routine ophthalmologic monitoring is not recommended

Referral

Manage patients in consultation with a nephrologist with expertise in AS (for treatment and monitoring recommendations)
Genetic counseling is recommended for patients requiring reproductive decision-making advice
Manage eye disease in consultation with an ophthalmologist with expertise in the specific underlying condition (eg, anterior lenticonus, posterior polymorphous corneal dystrophy)²³

Screening and Prevention

Screening

Case finding for first-degree relatives (eg, siblings, parents) of patients with AS
- Offer genetic counseling for possible genetic testing
- Consider annual urinalysis with referral to a nephrologist if urinalysis shows hematuria

Prevention

Preimplantation genetic testing is possible when familial pathologic variants responsible for disease are known

Use of AI Assistance

This content was prepared with the assistance of ChatGPT to format and proofread the manuscript for consistency, repetition, typographical errors, and potential inaccuracies. The author, as the subject matter expert, carefully reviewed and edited the content to ensure alignment with current evidence and clinical knowledge. The author takes full responsibility for the content of the publication

Author Affiliations

Catherine Quinlan, MB BAO BCh
Associate Professor
Department of Nephrology, The Royal Children’s Hospital, Melbourne, Australia
Kidney Genetics Team, Kidney Regeneration Group, Murdoch Children’s Research Institute
Department of Paediatrics, University of Melbourne

References

1.Zhao X, Chen C, Wei Y, et al. Novel mutations of COL4A3, COL4A4, and COL4A5 genes in Chinese patients with Alport syndrome using next generation sequence technique. Mol Genet Genomic Med. 2019;7(6):e653.