Immunofluorescence Microscopy

Standard immunofluorescence (IF) may show nonspecific trapping of immunoglobulin M (IgM) in the mesangium. Special IF studies for subtypes of type IV collagen on either skin or renal biopsy may be helpful in distinguishing between causes of thin glomerular basement membrane (GBM), which may be the only lesion in early Alport, the carrier state for Alport, or so-called benign familial hematuria (see below) (3,5,8-11).

In kidney biopsies, about 70% to 80% of males with X-linked Alport's lack staining of the GBM, distal tubular basement membrane, and Bowman's capsule for a3, a4, or a5 (IV) chains, and Bowman's capsule and distal tubular basement membrane (TBM) also show lack of a6 (IV) (3,10,11). In autosomal recessive Alport's, where a3 or a4 is mutated, the kidney GBMs usually show no expression of a3, a4, or a5, again because there is an inability to form the normal a3, a4, or a5 type IV collagen heterotrimer of the GBM. In these autosomal recessive cases, in contrast to X-linked cases, a5 and a6 remain strongly expressed in Bowman's capsule, distal tubular basement membrane, and skin, because the a (1)22/ (5)26 heterotrimers can still be assembled in these patients. Female heterozygotes for X-linked Alport's syndrome frequently show mosaic staining of GBM and distal TBM for a3, a4, and a5 (IV) chains, and skin mosaic staining for a5 (IV). Patients with autosomal dominant Alport's have not been studied immunohistochemically.

Of note, some cases with Alport's syndrome clinically and by renal biopsy showed apparent normal a5 type IV immunostaining pattern. About 20% of male classic Alport patients and affected homozygous autosomal recessive Alport patients show faint or even normal staining of the skin or GBM for a3 and a5 (3). This is postulated to reflect a mutation that results in protein, that albeit abnormal, still expresses the epitope recognized by the available antibodies. Thus, the absence of a5 type IV in the skin biopsy is helpful in indicating a basement membrane abnormality, but an apparent normal staining pattern in either skin or kidney does not definitively rule out Alport's syndrome (10,11). The possible continuum of Alport's syndrome with some cases of apparent benign familial hematuria with thin basement membranes further complicates interpretation of staining patterns (see below).

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