Abstract
Both thin basement membrane nephropathy (TBMN) and autosomal dominant Alport syndrome (ADAS) are types of hereditary nephritis resulting from heterozygous mutations in COL4A3 or COL4A4 genes. Although TBMN is characterized by hematuria and thinning of the glomerular basement membrane (GBM) with excellent renal prognosis, some patients develop end-stage renal disease (ESRD) later in life. In contrast, although AS is characterized by progressive nephropathy with lamellation of the GBM, there are some patients diagnosed with ADAS from a family history of ESRD but who only suffer from hematuria with GBM thinning. These findings indicate a limitation in distinction between TBMN and ADAS. Diagnosis of AS is significant because it facilitates careful follow-up and early treatment, whereas diagnosis of TBMN can underestimate the risk of ESRD. However, some experts are against using the term ADAS as the phenotypes of heterozygous variants vary from no urinary abnormality to ESRD, even between family members with the same mutations, indicating that unknown secondary factors may play a large role in the disease severity. These diagnostic difficulties result in significant confusion in clinical settings. Moreover, recent studies revealed that the number of patients with chronic kidney disease caused by these gene mutations is far higher than previously thought. The aim of this article is to review differing opinions regarding the diagnosis of heterozygous COL4A3 or COL4A4 variants, and to highlight the importance for nephrologists to recognize this disease, and the importance of the need to reclassify this disease to minimize the current confusion.
Highlights
Thin basement membrane nephropathy (TBMN) and Alport syndrome (AS) are common hereditary kidney diseases caused by structural abnormalities in the type IV collagen α-chains of glomerular basement membrane (GBM) [1, 2]
The diagnosis of patients with heterozygous mutations in COL4A3 or COL4A4 is controversial [7, 13–17, 35], resulting in confusion among nephrologists. This is primarily because the phenotype of heterozygous COL4A3 or COL4A4 variants varies from no urinary abnormality, to isolated hematuria, to end-stage renal disease (ESRD)
We recently reported that 69% of cases with adult nephritis accompanied by GBM thinning or thickening who were unable to receive accurate diagnosis clinicopathologically were diagnosed as autosomal dominant Alport syndrome (ADAS) by genetic analysis [12]
Summary
Thin basement membrane nephropathy (TBMN) and Alport syndrome (AS) are common hereditary kidney diseases caused by structural abnormalities in the type IV collagen α-chains of glomerular basement membrane (GBM) [1, 2]. The concept of two diseases was originally proposed based on clinicopathological features. Most individuals with TBMN present with hematuria, with or without mild proteinuria, and normal renal function with a diffuse thinning of the GBM. There are some patients with TBMN that develop end-stage renal disease (ESRD) in their later lives [3, 4]. AS is defined as progressive renal failure with irregular thickening and lamellation of the GBM, accompanied by hearing loss and ocular abnormalities [1]. Some patients with AS show renal impairment with only GBM thinning without lamellation, and lack of extrarenal manifestations [5–7]
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