Sindrome di Alport

Synonym: familial hereditary nephritis

This is a familial nephritis first described in 1927 by Cecil Alport. It comprises:¹

• Ematuria.

• Progressive chronic kidney disease (hereditary congenital haemorrhagic nephritis).

• Sensorineural hearing loss.

• Several ocular abnormalities.

It is a progressive disease that ultimately leads to malattia renale cronica. The altered glomerular basement membrane (GBM) functions adequately in early life. However, eventually there is the onset of proteinuria associated with the classic and progressive irregular thickening, thinning and splitting of the GBM, which culminates in end-stage kidney disease (ESKD).²

Epidemiologia

Alport's syndrome (AS) is rare; however, it does account for 3% of ESKD in childhood and is the most common of several types of hereditary nephritis.

Disease frequency is estimated at 1:5,000.³Males are more severely affected than females.

Inheritance is variable and may be either:⁴

• X-linked dominant - approximately 85%.

• Autosomal recessive - approximately 15%.

• Autosomal dominant - approximately 1%.

Different mutations in type IV collagen genes can lead to a broad spectrum of disease phenotypes.⁵ Up to 20% have no family history due to high spontaneous mutation rate.

Patogenesi

• AS is caused by defects in type IV collagen, a major structural component of the basement membranes in the kidney, ear and eye.

• X-linked AS is caused by defects in the COL4A5 gene which encodes collagen alpha-5 (IV) chain, located at Xq22.⁶

• Autosomal recessive AS is caused by mutations in either the COL4A3 or the COL4A4 gene.

• Accumulation of types V and VI collagen chains in the GBM occurs as a compensatory response.

• These proteins spread and result in GBM thickening and impairment of selectivity with subsequent glomerular sclerosis, interstitial fibrosis and chronic kidney disease.

AS associated with leiomyomatosis is a distinct entity. Diffuse leiomyomatosis of the oesophagus and tracheobronchial tree has been reported in some families with AS. Symptoms usually appear in adolescence and include dyspnoea, cough, stridor, recurrent bronchitis, dysphagia, vomiting and epigastric pain. The diagnosis is made by CT or MRI scanning.

Caratteristiche cliniche

• Progressive haematuric nephritis: microscopic haematuria is reported in almost 100% of patients with AS. Proteinuria is found in 85-95% of patients.⁷

• Sensorineural deafness: this feature is commonly, but not universally, observed in patients with AS. Hearing loss is never present at birth but usually becomes apparent by late childhood or early adolescence, generally before the onset of chronic kidney disease.

• Ocular abnormalities: lens - cataracts, microspherophakia, posterior or anterior lenticonus. Anterior lenticonus is the pathognomonic feature of AS. It is a slow, progressive deterioration of vision. Patients need to change the prescription of their glasses frequently. There is no eye pain, redness or night blindness.

A strong relationship has been demonstrated between mutations at the 5' end of the gene and younger age at onset of ESKD, hearing loss and ocular changes.⁷

Indagini

• Urinalysis:
  

  • Gross or microscopic haematuria is the most common and earliest sign in AS.

  • The condition is usually persistent in males, whereas it can be intermittent in females.

  • Proteinuria usually worsens with age.

• Microscopy: this shows a glomerular pattern of damaged red blood cells (RBCs) and RBC casts.

• Renal biopsy: light microscopy shows mesangial cell proliferation and capillary wall thickening, progressing to glomerular sclerosis and tubulo-interstitial changes.

• Electron microscopy: this shows GBM changes including splitting of lamina densa and lamellation.

• Gingival biopsy: changes in gingival tissues have been reported as a consequence of AS and may prove to be be an alternative initial diagnostic tool.⁸

Gestione

There is no definitive treatment for AS.

Control hypertension

This is usually present in males with X-linked AS and in males and females with autosomal recessive AS. Incidence and severity increase with age and degree of kidney disease.

Angiotensin-converting enzyme (ACE) inhibitors reduce proteinuria and progression of renal disease.⁹¹⁰They should be considered in patients with AS (particularly children) who have proteinuria with or without hypertension.¹¹

The addition of spironolactone to ACE-inhibitor treatment has been shown to reduce proteinuria significantly.¹²

Supportive management of chronic kidney disease

This may include dialysis and transplantation. Renal transplantation is not contra-indicated in patients with AS. Approximately 1-5% of patients with AS who undergo transplant develop anti-GBM nephritis.⁶ However, graft survival rates are excellent.

Consulenza genetica

Incomplete penetrance of AS in females must be considered; genetic tests may soon be available for gene-carrier status in most families.

Complicazioni

• Nephritic syndrome: oedema, hypertension, uraemia and oliguria.

• Sindrome nefrosica: oedema, hypoalbuminaemia, hyperlipidaemia.

• ESKD: occurs at an average age of 16-37 years.⁷

Prognosi

• Prognosis depends on the type of inheritance, the sex of the patient and the type of mutations in type IV collagen genes.

• Management during pregnancy can be very difficult and pregnancy is associated with a worsening of kidney disease.¹³