GlOMERULONEPHRITIS QUIZ

The answer to the GN quiz of June 8, 2012 is Alport's syndrome. The EM pic shows details of the peripheral capillary wall. Notice the extreme fragmentation of the lamina densa, resulting in a characteristic “basket weave” pattern.

The Question

A 22-year-old white male presents with a history of microscopic hematuria and albuminuria. He also complains of a steady deterioration in his hearing, accompanied intermittently by low-pitched tinnitus in both ears in the past 5 years. Family history is notable for an uncle who developed kidney failure. Pure-tone audiometry with speech testing confirmed bilateral moderate sensorineural hearing loss. Complete blood count showed normal values. Blood urea nitrogen (BUN) and creatinine levels were elevated at 42 and 2.6 mg/dL, respectively. Chest X-ray and ECG were normal. Ultrasound of the kidneys was normal. A percutaneous kidney biopsy showed the following electron micrograph (see pic). What is the diagnosis?

Explanation

Alport syndrome (AS) is an inherited disorder clinically presenting with the classic triad of progressive glomerulonephritis, progressive high-tone hearing loss, and several ocular signs, the most pathognomonic of which is the presence of anterior lenticonus.

Cecil A. Alport first described this disease extensively in 1927, although initial reports had previously been described several times, foremost by Guthrie in 1902.

Alport studied 3 generations of a family with hereditary nephritis and deafness and noted that the most common presenting symptom was macroscopic hematuria. The eponym Alport syndrome (AS) was coined in 1961.

Alport syndrome is most commonly inherited as an X-linked disorder, accounting for approximately 80 to 85% of familial cases. The rest of these cases are inherited in either an autosomal recessive or dominant pattern, and the clinical course and manifestation may be different from the X-linked variant.

The overall gene frequency of Alport syndrome is estimated at ≈ 1 in 5,000. The incidence is between 1: 5,000 and 1:10,000, while the prevalence is ≈ 1 in every 50,000 live births.

AS leads to renal replacement therapy in ≈1 to 2% of patients in Europe and 2.3% of the transplant population in the United States. AS comprises ≈2.7% of all patients with pediatric end-stage renal disease (1999 United States Renal Data System annual data report).

All forms of Alport syndrome are caused by mutations in the COL4A5 collagen gene, giving rise to defective type IV collagen, which is a major structural component of basement membranes in the body, including those found in the lens, glomeruli, and cochlea. This results in a failure of maturation of collagen in these areas, leading to diffuse thickening of glomerular basement membranes, and abnormalities of the cochlea and lenses of the eye.

Six type IV collagen genes have been cloned and characterized, and are localized in pairs on three chromosomes, namely chromosome 13, 2, and the X chromosome. Full expression of Alport syndrome requires a mutation in the COL4A5 allele, which is carried by males with X-linked disease, or mutations in both alleles of COL4A3 or COL4A4 in either males or females carrying the autosomal recessive form.

X-linked AS is responsible for approximately 85% of all familial cases.

• Males tend to be more severely affected than females.
• AS typically starts in children or young adults as asymptomatic, persistent microhematuria, which is the most common manifestation of this disease, occurring in 100% of affected individuals and in about 90% of carriers.
• Gross hematuria may occasionally occur in males together with flank pain or abdominal discomfort. Mild proteinuria and hearing loss defined as high-frequency sensorineural deafness are usually present at the time of diagnosis, as well as the deterioration in vision due to structural lens abnormalities leading to a significantly high axial myopia.
• Sensorineural deafness occurs in approximately 80% of cases and ocular findings have been reported in roughly 40%.
• End-stage renal disease (ESRD) happens in 50% of affected males usually by the age of 25 and in 15% of carriers before the age of 50.
• Renal prognosis depends on the kind of mutation. The probability of ESRD occurring in patients younger than 30 years is significantly higher (90%) when they have a 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 females with XLAS developing ESRD 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 visible with electron microscope.
• Hematuria is usually discovered during the first years of life in males with Alport syndrome. If individuals do not have hematuria during the first decade of life, they are unlikely to have Alport syndrome.
• Proteinuria is usually absent in childhood, but this condition eventually develops in males with XLAS and in both males and females with ARAS.
• Hearing loss and ocular abnormalities are never present at birth and usually become apparent by late childhood or early adolescence, generally before the onset of renal failure.
• Hypertension is a late finding.

No definite treatment exists for Alport syndrome.

Gene therapy for Alport syndrome is being studied. Animal studies are underway to evaluate the delivery of human alpha-5 (IV) chain of GBM in a canine model of X-linked Alport syndrome.

Sources emedicine and Tiuseco, et al