Thin glomerular basement membrane disease

Kidney International, Vol. 60 (2001), pp. 799–800
EDITORIAL
Thin glomerular basement membrane disease
Isolated microscopic hematuria that begins in childhood and is of glomerular origin has a rather limited
differential diagnosis, with Alport syndrome, IgA nephropathy, and benign familial hematuria as the most
prevalent conditions. In a series of 322 children with
persistent hematuria for longer than 6 months, biopsies
were classified as IgA nephropathy in 78 patients, Alport
syndrome in 86 patients, and thin basement membrane
nephropathy in 50 patients. The biopsies in 48 patients
showed normal glomeruli and one patient had a more
rare disorder [1].
Patients with benign familial hematuria usually have
persistent hematuria, although intermittent hematuria
does occur in some patients. Episodic gross hematuria
is rare. Proteinuria, progression to renal failure, or extrarenal symptoms such as hearing loss are not present.
Thinning of the glomerular basement membrane (GBM),
the hallmark of this disease, is usually uniform, but focal
alteration involving at least 50% of the GBM may occur.
To define thin GBM disease, it is important to realize
that the thickness of the GBM depends on the age and
gender of the patient. The most extensive study of GBM
thickness in children was performed by Morita et al, who
calculated thickness from 100 to 340 nm at 1 year of age
to 190 to 440 nm at 9 years of age and older [2]. Dische
found that the GBM is thinner in female patients than
in male patients [3]. Considering the differing results
obtained by investigators, the conclusion by Dische that
a local “normal range” should be established in each
unit is appropriate.
Thin glomerular basement can sometimes be associated with other glomerulopathies [4, 5]. Coleman and
Stirling noted GBM thinning in minimal-change disease
[6]. In an unpublished study of 37 children with minimalchange nephrotic syndrome, investigators in our unit demonstrated that 65% of the patients had thin segments of
more than 5% and 37% of the patients with more than
15%, respectively, of the GBM [M te Loo, unpublished
observation, 2000].
Thin GBM disease begs for a molecular explanation.
The attenuation of the GBM, as such, is not the cause
of the hematuria. By morphometric analysis of newly
transplanted kidneys, Dische et al were able to demon-
strate that thin basement membranes were present in
between 5.2 and 9.2% of the general population [7]. An
important step in this investigation was the demonstrated
segregation of biopsy-proved thin GBM disease with the
locus for autosomal-recessive Alport syndrome in 8 of
22 families [8]. In this issue of Kidney International, the
same investigators showed a heterozygote mutation in
Col4A4 gene in thin GBM disease [9]. Additional molecular abnormalities can be expected and should allow a
clearer delineation of thin GBM disease.
What should be the strategy when a diffuse thin GBM
is found in a patient with isolated hematuria? In most
kindred with benign familial hematuria, autosomal-dominant inheritance is observed. However, in a few families,
the inheritance appears to be autosomal-recessive or it
occurs sporadically. An X-linked Alport syndrome can
mostly be excluded based on the inheritance pattern. A
diffuse thinning of the GBM was the only abnormality
seen in a 15-year-old boy with X-linked Alport syndrome
[10]. However, the autosomal-recessive form of Alport
syndrome caused by mutation in COL4A3 or COL4A4
genes (found in approximately 14% of the cases) and
the recently described autosomal-dominant form caused
by COL4A3 mutation [11] remain a possibility. Hopefully, aberrant laminin ␣2 deposition in GBM, as is present in X-linked and autosomal-recessive forms of Alport
syndrome [12], will not be found in thin GBM disease.
Leo A.H. Monnens
Nijmegen, The Netherlands
Correspondence to Leo A.H. Monnens, M.D., Department of Pediatric Nephrology, University Hospital Nijmegen, Nijmegen HB 6500, The
Netherlands.
E-mail: [email protected]
REFERENCES
1. Piqueras AI, White RHR, Raafat F, et al: Renal biopsy diagnosis
in children with hematuria. Pediatr Nephrol 12:386–391, 1998
2. Morita M, White RHR, Raafat F, et al: Glomerular basement
thickness in children. Pediatr Nephrol 2:190–195, 1988
3. Dische FE: Measurement of glomerular basement membrane
thickness and its application to the diagnosis of thin-membrane
nephropathy. Arch Pathol Lab Med 116:43–49, 1992
4. Cosio FG, Falkenhain ME, Sedmak DD: Association of thin
glomerular basement membrane with other glomerulopathies. Kidney Int 46:471–474, 1994
5. Auwardt R, Savige J, Wilson D: A comparison of the clinical
and laboratory features of thin basement membrane disease and
IgA glomerulonephritis. Clin Nephrol 52:1–4, 1999
6. Coleman M, Stirling JW: Glomerular basement membrane thinning is acquired in minimal change disease. Am J Nephrol 11:437–
438, 1991
Key words: thin glomerular basement membrane, alport syndrome,
benign familial hematuria
 2001 by the International Society of Nephrology
799
800
Editorial
7. Dische FE, Anderson VER, Keane SJ, et al: Incidence of thin
membrane nephropathy: morphometric investigation of a population sample. J Clin Pathol 43:437–460, 1990
8. Buzza M, Wilson D, Savige J: Segregation of hematuria in thin
basement membrane disease with haptotypes at the loci for Alport
syndrome. Kidney Int 59:1670–1676, 2001
9. Buzza M, Wang YY, Dagher H, et al: Col4A4 mutation in thin
basement membrane disease previously described in Alport syndrome. Kidney Int 60:480–483, 2001
10. Rizzoni G, Massella L, Muda AO: ␣5 COL IV chain distribution
in glomerular basement membrane in a male with X-linked Alport
syndrome and thin basement membrane. Pediatr Nephrol 15:325,
2000
11. Van der Loop FTL, Heidet L, Timmer E, et al: Autosomal dominant Alport sydrome caused by a COL4A3 splice site mutation.
Kidney Int 58:1870–1875, 2000
12. Kashtan CE, Kim Y, Lees GE, et al: Abnormal glomerular basement membrane laminins in murine, canine, and human Alport
syndrome: Aberrant laminin ␣2 deposition is species independent.
J Am Soc Nephrol 12:252–260, 2001

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