Familial benign hematuria N02.9

Synonyms

Thin basement membrane disease; TBMD; thin basement membrane disease; thin basement membrane nephropathy; thin basement membrane disease; TBMN; nephropathy with thin glomerular basement membrane; benign familial hematuria; type IV collagen-associated nephropathy;

First described

In 1966, McConville and McAdams were the first to describe a group of children with micro-hematuria that also affected other family members. Typically, however, they were not found to have nephropathy. They were the first to coin the term "benign familial hematuria." With the advent of electron microscopy in the 1970s, changes in the glomerular basement membrane could be described in this clinical picture (Plenova 2017).

After the 1970s, the term "thin membrane syndrome" was introduced (Plenova 2017).

In 2018, the following diagnoses were grouped under the umbrella term of "type IV associated disorders":

- benign familial hematuria

- thin basement membrane syndrome

- classic Alport syndrome (Brunkhorst 2021)

Familial hematuria (TBMN) is a hereditary disorder with autosomal dominant inheritance resulting in isolated glomerular micro-hematuria (Herold 2022). The term TBMN is derived from histopathology (Comic 2022).

TBMN belongs to the phenotypically and genetically complex disease of type IV collagen-associated nephropathy. In addition to TBMN, this includes various phenotypes such as Alport syndrome and focal segmental glomerulosclerosis = FSGS. The mode of inheritance of type IV collagen-associated nephropathy is both autosomal dominant and X chromosomal (Comic 2022).

TBMN is the most common cause of familial microscopic hematuria. The incidence is approximately 1% (Plenova 2017).

TBMN is a hereditary disease. Rarely, sporadic cases occur in which a de novo mutation is present (Plenova 2017). The penetrance of hematuria is approximately 70% (Savige 2013).

TBMN is usually caused by a heterozygous COL4A3 or COL4A4 mutation (Savige 2013). The mutation can also cause late-onset focal segmental glomerulosclerosis (FSGS) or autosomal dominant Alport syndrome (ADAS) (Hirabayashi 2022).

Mutations in the collagen type 4A3 gene, 4A4 gene and 4A5 gene lead to mechanical instability of the glomerular basement membrane. Characteristic lamellation and splitting of the membrane occurs (Brunkhorst 2021).

The thickness of the glomerular basement membrane is age-dependent and varies between individual laboratories. A thickness of < 150 nm is considered dilute by convention (Plenova 2017).

The disease usually manifests itself in childhood (Kasper 2015).

Affected patients are asymptomatic. Often, recurrent and persistent hematuria is found as an incidental finding (Plenova 2017). However, proteinuria, deterioration of renal function, and arterial hypertension are typically absent (Kasper 2015).

TBMN is usually initially suspected clinically. A biopsy should only be performed in the presence of atypical features such as proteinuria > 1.0 g / d, existing renal dysfunction, etc. (Savige 2013).

The diagnosis can be confirmed based on evidence of a thinned glomerular basement membrane (Savige 2013). The normal value of the basement membrane is between 300 - 350 nm, but differs between individual laboratories and decreases with age. A thickness of < 150 nm is considered dilute by convention (Plenova 2017).

From labor-intensive and expensive genetic tests, only COL4A5 mutation (evidence of X- chromosomal Alport syndrome) should be excluded (Savige 2013).

Genetic defects in type IV collagen are found (Kasper 2015). In < than 10% of carriers, microscopic hematuria is not detectable, indicating incomplete penetration (Plenova 2017).

Alport syndrome, a rare hereditary nephritis (Kasper 2015) with X chromosomal or autosomal dominant inheritance (Hirabayashi 2022).

In this case, in addition to hematuria, there is proteinuria, arterial hypertension, chronic renal failure, and extrarenal changes. In preschool and elementary school age, Alport syndrome also initially manifests as thinning of the basement membrane (Plenova 2017).

Alport syndrome and TBMN are clinically and structurally indistinguishable. The COL4A5 pathogenic variant shows a high sensitivity of >90% and high specificity for Alport syndrome (Savige 2013).

In TBMN, gravidity does not pose a risk (Plenova 2017).

If patients with TBMN have poor prognostic indicators such as arterial hypertension, renal dysfunction, and proteinuria, treatment by a nephrologist is recommended (Savige 2013).

Medication to delay renal failure is ACE inhibitors.

The prognosis of TBMN was previously thought to be good (Kasper 2015). However, in recent years, it has been shown that a significant percentage (approximately 33%) of patients with isolated TBMN develop proteinuria and deterioration of renal function in advanced age (Pecovnik 2021), up to autosomal dominant Alport syndrome (Hirabayashi 2022).

In patients with TBMN, renal failure exists in only a few aged >50 years, whereas in Alport syndrome, 90% of those <40 years are on dialysis (Comic 2022).

Recently, reports have increased that 20-30% of heterogeneous carriers of TBMN develop end-stage renal disease (ESRD) by the age of 70 years and develop further extrarenal manifestations. From there, genetic counseling of affected patients is recommended (Plenova 2017).

Patients with TBMN should be screened 1 x / a for arterial hypertension, proteinuria and renal dysfunction (Plenova 2017).

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