Thin-basement-membrane nephropathy (Hematuria, benign familial)

Thin basement membrane type nephropathy (TBMN), often referred to as benign familial hematuria, is observed in approximately 1% of the population and is characterized by persistent glomerular hematuria and minimal proteinuria with normal renal function. The prognosis is generally considered good, but end-stage renal failure may develop in some patients. TBMN is inherited in an autosomal dominant manner, with pathogenic changes detected in the COL4A3 and COL4A4 genes in heterozygous form.

Alport syndrome (ATS), which is characterized by glomerular haematuria and progressive proteinuria and leads to terminal renal failure, can also be associated with extrarenal changes such as sensorineural hearing loss and eye changes (anterior lenticonus). It is also caused by changes in the COL4A3, COL4A4 (autosomal recessive and autosomal dominant inheritance) and COL4A5 (X-linked inheritance) genes. However, polymorphic COL4A5 variants have also been detected, which in some cases can cause the phenotype of TBMN instead of ATS.

Patients with TBMN are considered carriers for autosomal recessive ATS. Renal biopsy is of great importance in differentiating between the two entities, but in the early stages of ATS it is often not possible to differentiate it histologically from TBMN. Children whose parents both suffer from TBMN and each carry a heterozygous mutation in COL4A3 or COL4A4 can inherit both variants with a probability of 25% and therefore develop Alport syndrome. For this reason, heterozygosity for the autosomal recessive form of Alport syndrome can be assumed in the presence of TBMN.

References

Kajimoto et al. 2019, Clin Exp Nephrol 23:638 / Savige et al. 2019, Pediatr Nephrol 34:1175 / Papazachariou et al. 2017, Clin Genet 92:517/ Weber et al. 2016, Pediatr Nephrol 31:941 / Pierides et al. 2013, Hippokratia 17:207 / Voskarides et al. 2009, J Am Soc Nephrol 18:3004 / Marcocci et al. 2009, Nephrol Dial Transplant 24:1464 / Hou et al. 2007, Am J Nephrol 27:538 / Hudson et al. 2003, N Engl J Med 348:2543