Alport Syndrome Clinical Overview
Alport Syndrome: A High-Yield Clinical Monograph
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: Alport syndrome is the second most common inherited cause of chronic kidney disease (CKD) after ADPKD. You will encounter these patients in nephrology clinics, paediatric renal clinics, and when they present with end-stage renal failure (ESRF) at a young age. Identifying it early is critical for genetic counselling and slowing renal progression.
High-Yield Definition: Alport syndrome is a genetic disorder of Type IV collagen synthesis, arising from mutations in the COL4A3, COL4A4, or COL4A5 genes. This results in a progressive nephropathy, often associated with sensorineural hearing loss and specific ocular abnormalities.
Clinical One-Liner: "It's the young male patient with persistent microscopic haematuria, high-frequency hearing loss, and funny-looking eyes, who has multiple male relatives on dialysis."
II. Etiology & Risk Factors
Etiology:
A genetic defect in the alpha-chains of Type IV collagen, a key structural component of the glomerular basement membrane (GBM), cochlea, and lens.
Risk Factors:
The primary risk factor is a positive family history. Ask specifically for:
Family history of Alport syndrome.
Family history of "kidney failure" or dialysis, especially in male relatives.
Family history of persistent haematuria or deafness.
III. Quick Pathophysiology
The defective Type IV collagen leads to an unstable GBM. Over time, this basement membrane progressively splits, thickens, and lamellates (the "basket-weave" appearance on electron microscopy). This structural failure causes:
Kidney: Allows red blood cells and protein to leak through (haematuria, proteinuria). This triggers progressive glomerulosclerosis and interstitial fibrosis, leading to ESRF.
Ear: Affects collagen in the cochlea (stria vascularis), leading to progressive, bilateral sensorineural hearing loss (SNHL).
Eye: Affects the lens capsule, cornea, and retina. The most specific sign is anterior lenticonus (a conical protrusion of the anterior lens surface).
IV. Classification
Classification is based on the mode of inheritance, which dictates prognosis:
X-linked (XLAS): ~85% of cases. Due to
COL4A5mutation. It is severe in affected males. Female carriers have a variable course, from asymptomatic haematuria to ESRF in later life.Autosomal Recessive (ARAS): ~10-15% of cases. Due to two mutations in
COL4A3orCOL4A4. Affects males and females with equal severity, phenotypically similar to XLAS in males.Autosomal Dominant (ADAS): ~5% of cases. Due to one mutation in
COL4A3orCOL4A4. This form is typically the mildest, often presenting with haematuria but slow or rare progression to ESRF.
V. Clinical Assessment
🚩 Red Flags & Immediate Actions
This is a chronic condition. Red flags relate to its complications:
Uraemic Symptoms (e.g., confusion, persistent vomiting, pericardial rub): Signifies ESRF. Action: Urgent renal profile, check for hyperkalaemia/acidosis, escalate to nephrology for urgent RRT.
Sudden Vision Loss: May suggest lens dislocation (from lenticonus) or macular hole. Action: Urgent ophthalmology referral.
Hypertensive Emergency: Can occur with progressive renal failure. Action: Manage as per CPG (e.g., IV labetalol, admit).
History
Key Diagnostic Clues (The Triad):
Renal: Persistent microscopic haematuria (often since childhood). May have episodes of gross haematuria, especially after a URI. Frothy urine (proteinuria).
Hearing: Progressive difficulty hearing, especially high-frequency sounds. Family members may have noticed it first.
Visual: Gradually worsening vision (related to lenticonus).
Symptom Breakdown:
Common (>50%): Persistent microscopic haematuria. Family history of ESRF.
Less Common (10-50%): Bilateral high-frequency SNHL (develops in late childhood/adolescence), hypertension, progressive proteinuria, episodic gross haematuria.
Rare (<10%): Ocular symptoms, anterior lenticonus, peripheral retinopathy (dot-and-fleck), corneal erosions. Diffuse leiomyomatosis (benign smooth muscle tumours of oesophagus/trachea) is a very rare syndromic variant.
Pertinent Negatives:
No systemic symptoms (fever, rash, joint pain) - argues against lupus nephritis or vasculitis.
No recent pharyngitis with low C3 - argues against post-strep GN.
No palpable purpura - argues against IgA vasculitis (HSP).
Physical Examination (OSCE Approach)
General Inspection: May appear well, or show signs of advanced CKD (pallor, sallow skin, cachexia, uraemic fetor).
Vitals: Check BP (hypertension is a key feature of progression).
Disease-Specific Examination:
Renal/Systemic: Check for fluid status: pedal oedema, periorbital oedema, raised JVP, lung base crackles.
ENT: Gross hearing test (whisper test, Rinne/Weber). This is insufficient; formal audiometry is required.
Ophthalmology: Visual acuity. Fundoscopy (may see retinal flecks). Direct ophthalmoscopy may reveal the "oil droplet" sign, a reflex from the anterior lenticonus. This requires a slit-lamp exam by ophthalmology to confirm.
Pertinent Negatives: No butterfly rash (SLE), no abdominal masses (PKD).
Clinical Pearl: In any young male patient (child or young adult) presenting with persistent haematuria, especially with a family history of kidney failure, Alport syndrome must be a top differential. Your job is to screen for the extra-renal features (hearing and eyes).
VI. Diagnostic Workflow
Differential Diagnosis
IgA Nephropathy (Berger's Disease):
Points For: Most common GN. Presents with haematuria (often gross, syn-pharyngitic).
Points Against: No extra-renal features (no SNHL, no lenticonus). Family history is less common.
How to Differentiate: Renal biopsy (IF shows mesangial IgA deposits).
Thin Basement Membrane Disease (TBMD):
Points For: Persistent microscopic haematuria, often with a strong family history.
Points Against: Non-progressive. No proteinuria, no hypertension, no ESRF, no extra-renal features.
How to Differentiate: This is often caused by a heterozygous
COL4A3/A4mutation (i.e., a carrier state for ARAS). Biopsy shows only thinning of the GBM, without the classic lamellation/splitting seen in Alport.
Lupus Nephritis:
Points For: Can present with haematuria, proteinuria, and renal failure.
Points Against: Predominantly female. Presence of systemic inflammatory symptoms (rash, arthritis). No SNHL/lenticonus.
How to Differentiate: Serology (ANA, anti-dsDNA, C3/C4).
Investigations Plan
Bedside / Initial:
UFEME: Persistent microscopic haematuria is the hallmark. Proteinuria will be present and will worsen with disease progression.
BP: Check for hypertension.
First-Line Labs & Imaging:
Renal Profile (Urea, Creatinine, eGFR): To stage CKD.
Urine Protein-to-Creatinine Ratio (UPCR): To quantify proteinuria. This is the key marker for prognosis and response to treatment.
FBC: May show anaemia of chronic disease.
Renal Ultrasound: Usually non-specific, shows bilateral echogenic kidneys (medical renal disease) or small kidneys in late-stage.
Specialised Workup (For Diagnosis):
Audiometry: To detect characteristic bilateral high-frequency sensorineural hearing loss.
Ophthalmology Slit-Lamp Exam: To look for pathognomonic anterior lenticonus, as well as retinal flecks or corneal dystrophy.
Confirmatory / Gold Standard:
Genetic Testing: Sequencing of
COL4A3,COL4A4, andCOL4A5. This is now the preferred first-line confirmatory test if available. It is non-invasive and provides prognostic information.Renal Biopsy: Required if genetic testing is unavailable or inconclusive.
Light Microscopy: Often non-specific. May be normal early, shows focal segmental glomerulosclerosis (FSGS) and interstitial fibrosis later.
Immunofluorescence (IF): Negative. This is crucial to rule out immune-complex GNs (like IgA or Lupus).
Electron Microscopy (EM): This is the classic diagnostic finding. Shows thickening, splitting, and lamellation of the GBM, described as a "basket-weave" pattern.
VII. Staging & Severity Assessment
Staging follows the standard KDIGO CKD classification (based on eGFR and albuminuria).
Prognosis and severity are dictated by the genotype:
Severe Phenotype: Typically XLAS males with "major" mutations (large deletions, nonsense). High risk of ESRF by age 20-30.
Intermediate Phenotype: XLAS males with "minor" mutations (missense). ESRF often by age 40-50.
Variable Phenotype: XLAS females. Most have haematuria, but ~15-30% will progress to ESRF by age 60.
Mild Phenotype: ADAS. Progression to ESRF is rare.
The single most important clinical marker of severity is the degree of proteinuria.
VIII. Management Plan
A. Principle of Management
There is no cure. Management is centred on:
Slowing the progression of CKD.
Managing complications (hypertension, proteinuria).
Managing extra-renal manifestations (hearing, vision).
Genetic counselling.
B. Immediate Stabilisation (The ABCDE Plan)
This is not relevant for the chronic diagnosis of Alport syndrome itself. Management is focused on acute complications, such as hypertensive emergency or acute pulmonary oedema from fluid overload, which should be managed per standard protocols.
C. Definitive Treatment (The Ward Round Plan)
First-Line (Disease-Modifying): RAAS Blockade
Drug: ACE inhibitors (e.g., Perindopril, Enalapril) or ARBs (e.g., Losartan).
Indication: Must be started as soon as proteinuria (or even microalbuminuria) is detected, even if the patient is normotensive.
Dose: Start low, titrate up to the maximum tolerated dose.
Goal: Reduce proteinuria as much as possible and maintain BP < 130/80 mmHg. This is proven to delay the onset of ESRF by years.
Second-Line (Add-on Therapy): SGLT2 Inhibitors
Drug: E.g., Dapagliflozin, Empagliflozin.
Indication: Add-on to maximally tolerated ACEi/ARB for patients with persistent proteinuria (UPCR > 20 mg/mmol), as per the Malaysian CPG for CKD (based on DAPA-CKD/EMPA-KIDNEY trials).
Supportive Management:
Strict BP Control: Target < 130/80 mmHg.
Lipid Control: Statins as per CPG guidelines for CKD.
Diet: Low-salt diet (<2g/day). Protein restriction in advanced CKD.
Renal Replacement Therapy (RRT):
Plan for dialysis (HD or PD) or renal transplantation when eGFR approaches 15-20 ml/min/1.73m2.
Transplantation has excellent outcomes. Note: A small risk (~3-5%) of developing anti-GBM disease in the allograft exists, as the patient's immune system sees the "normal" Type IV collagen in the new kidney as foreign.
D. Long-Term & Discharge Plan
This requires a multidisciplinary team (MDT).
Nephrology: Lifelong follow-up (3-6 monthly) to monitor BP, renal profile, and UPCR. Titrate medications.
Audiology: Regular (annual) hearing screening. Fit for hearing aids when SNHL becomes symptomatic.
Ophthalmology: Regular (annual) screening for lenticonus, cataracts, and retinopathy. May require cataract surgery.
Genetic Counselling: Essential for the patient and their family. Discuss inheritance patterns, family planning, and cascade screening of at-risk relatives (e.g., urinalysis for haematuria in the patient's mother, sisters, and children).
IX. Complications
Immediate/Short-Term: Complications of nephrotic-range proteinuria (e.g., oedema, VTE), hypertensive urgency.
Long-Term:
Progressive CKD leading to End-Stage Renal Failure (ESRF).
Progressive bilateral sensorineural deafness.
Ocular: Cataracts (from lenticonus), macular holes, visual impairment.
Rare: Leiomyomatosis (oesophageal, tracheobronchial).
X. Prognosis
Untreated XLAS Males: 50% risk of ESRF by age 25; 90% by age 40.
Treated XLAS Males: Early and sustained ACEi therapy can delay ESRF by 10-20 years.
XLAS Females: Highly variable. Most only have haematuria. ~15-30% develop ESRF by age 60.
ARAS: Similar severe prognosis to XLAS males for both sexes.
Key Prognostic Factors: Genotype, sex, degree of proteinuria, and BP control.
XI. How to Present to Your Senior
Situation: "Doctor, I'm calling to discuss a 19-year-old male, a new referral to the nephrology clinic for persistent haematuria and proteinuria."
Background: "He was found to have haematuria on a pre-university check-up. Family history is significant for his maternal uncle who started dialysis at age 30. His audiometry shows bilateral high-frequency SNHL, and ophthalmology confirms anterior lenticonus."
Assessment: "His BP is 145/90. UFEME shows 3+ blood, 2+ protein. UPCR is 150 mg/mmol. His eGFR is 75 ml/min/1.73m2. My working diagnosis is Alport Syndrome, likely X-linked."
Recommendation: "My plan is to start him on Perindopril 2mg OD and titrate up, aiming for BP <130/80 and maximal proteinuria reduction. I will also arrange for genetic testing to confirm the subtype and for him to see the genetic counsellor. I will give him a 3-month follow-up appointment."
XII. Summary & Further Reading
Top 3 Takeaways:
Suspect Alport: Always suspect in a patient (especially male) with haematuria and a family history of ESRF or deafness.
Look for the Triad: It's a multi-system disease. If you find haematuria, you must screen for SNHL (audiometry) and ocular signs (ophthalmology referral).
Treat Early: The cornerstone of management is early and aggressive RAAS blockade (ACEi or ARB) to slow CKD progression. Start as soon as proteinuria is detected.
Key Resources:
Local CPG: Malaysian CPG for Management of Chronic Kidney Disease (2018). (Used for general principles of CKD and proteinuria management).
UpToDate: "Genetics, pathogenesis, and diagnosis of Alport syndrome (hereditary nephritis)" and "Management of Alport syndrome".
Review Article: Kashtan, C. E. (2021). Alport syndrome. Nature Reviews Disease Primers, 7(1), 69.
