Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
Address correspondence to: Dr. Karl Tryggvason, Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, Stockholm S-171 77, Sweden. Phone: +46-8-5248-7720; Fax: +46-8-31-6165; E-mail: karl.tryggvason{at}ki.se
Thin basement membrane nephropathy (TBMN) is the most commoncause of persistent hematuria in children and adults, the othermain causes being IgA nephropathy and Alport syndrome (1–3).In addition to hematuria, patients with TBMN usually have minimalproteinuria, normal renal function, and uniformly thinned glomerularbasement membranes (GBM), as determined by electron microscopy.TBMN, which affects at least 1% of the population, is a lifelongnonprogressive disorder associated with family history. TBMNwas first described approximately 80 yr ago as a curable formof hemorrhagic nephritis (4). Later, many cases of this microscopic,painless hematuria with good prognosis were shown to be inherited,and this fact is emphasized in the numerous names used for thedisease in the literature, such as "congenital hereditary hematuria"(5), "hereditary hematuria" (6), "familial hematuric nephritis"(7), "familial benign hematuria" (8), "benign familial hematuria"(9,10), "familial benign essential hematuria" (11,12), "benignhereditary nephritis" (13), and "benign essential hematuria"(14). TBMN has also been referred to as familial hematuria (15),but that is a misnomer, as it does not distinguish it from theprogressive Alport syndrome (3). Commonly used names are "thinmembrane nephropathy" (16–18), "thin basement membranedisease" (19–25), "thin GBM nephropathy" (26), and "thinGBM syndrome" (27). The term "thin basement membrane nephropathy"is currently most widely used (1,2,28–36), and this nameis to be preferred, as it refers to a renal disorder that isassociated with observable structural changes in the basementmembrane (3) without necessarily being a "true disease."
It has been and still is a major clinical challenge to differentiatebetween TBMN characterized by nonprogressive hematuria and Alportsyndrome with progressive hematuria as the main symptom. Theconnection between recurrent benign hematuria and thin GBM wasfirst noted in electron microscopic analysis of kidney specimensin 1973 (11). This typical histopathologic feature of TBMN,i.e., uniform thinning of the GBM, could be found also at theearly stages of Alport syndrome, which suggested that the pathomechanismsof the two diseases might overlap. This connection was verifiedat the gene level during the early 1990s, when the type IV collagengenes COL4A3, COL4A4, and COL4A5 were discovered and shown tobe mutated in X-linked and autosomal Alport syndromes (37–41),with subsequent demonstration of mutations in COL4A3 and COL4A4in TBMN (10). At present, 40% of TBMN cases have been associatedwith the COL4A3 and COL4A4 genes (23,42), but it remains tobe verified whether female carriers who are carriers for a mutationin the COL4A5 gene can develop true TBMN. In principle, DNA-baseddiagnosis of TBMN is possible, but such tests are not commerciallyavailable. At present, the clinical diagnosis still is mademainly on the basis of persistent hematuria with minimal proteinuriaand normal renal function, combined with electron microscopyexamination of biopsy showing thinned GBM; the use of immunologicexamination of the type IV collagen 3 to 5 chains still is notbeing used extensively. However, as discussed below, these methodsare insufficient; therefore, the majority of TBMN cases arestill considered to be undiagnosed.
TBMN has been reported in all races, although most of the casesthus far have been reported in developed countries. Hematuriahas been diagnosed at all ages (8,11,43), and several studieshave indicated that the disease is somewhat more common in femalethan in male individuals, among both children and adults (8,17,18,27,42–47),but other studies have not revealed such findings (26,48–50).Exact prevalence of the disease is difficult to assess, as thediagnosis is made mostly on the basis of persistent hematuriacombined with minimal proteinuria, whereas the number of electronmicroscopic analyses of renal biopsies showing thinned basementmembrane have become less common (51). Thus, most of the casesremain undiagnosed. However, the prevalence may be estimatedfrom known frequencies of persistent hematuria in the populationand from the number of TBMN cases in archival series of renalbiopsies, together with the knowledge of prevalence of autosomalAlport syndrome (51). Several studies have addressed the prevalenceof hematuria and persistent hematuria in children and adults(52–56). Persistent hematuria is commonly defined as hematuriathat is observed on at least two occasions, and in TBMN, a usefuladditional criterion could be that these two incidents occurredat least 2 yr apart (51). Persistence of hematuria is importantfrom the point of view of TBMN diagnosis, as it distinguishesfrom other, more acute renal disorders, such as hematuria associatedwith streptococcal infections (51). The prevalence of hematuriain children has been estimated to be 1 to 2% (52,53), but theprevalence in adults is not well known (3). According to Wangand Savige (51), persistent hematuria occurs consistently inas much as 6% of both children and adults. On the basis of bothdirect and indirect approaches, the overall prevalence of TBMNin the population has been estimated to be 1% (3). However,on the basis of observations of frequencies of persistent hematuria,thin basement membrane in renal biopsies, and autosomal recessiveAlport syndrome, another estimate indicates a higher prevalenceof >1 but <10% (51). When making estimations about theprevalence of TBMN by analyzing incidence of hematuria, oneshould keep in mind that not all patients who have TBMN havehematuria (or it is intermittent), that some patients with persistenthematuria have other signs of renal impairment (excluding thediagnosis of TBMN), and last that hematuria is not always ofglomerular origin. It can be concluded, however, that TBMN isthe most common inherited renal disorder.
The characteristic clinical manifestation of TBMN is persistentmicroscopic hematuria (1–3,8,11,16,17,26,27,43,44,46,57).Most patients with TBMN present only with hematuria, withoutadditional symptoms or progression to renal impairment, andthe condition is usually incidentally detected during healthcontrol. The age at diagnosis varies considerably, from as earlyas age 1 yr (8,43) up to age 86 yr (11). TBMN, which does notprogress, has been documented for up to 30 yr (17). Microscopicanalysis of the urine samples reveals red blood cells in mostpatients. At least a single episode of macroscopic hematuriais observed in 5 to 22% of patients, typically manifesting afterexercise or during infection. However, occurrence of macroscopichematuria seems to be more common in patients with Alport syndromeand IgA nephropathy (45,57). The urinary blood cells are dysmorphicwith irregular shape and size, indicating hematuria of glomerularorigin (17,18). Occasionally, the hematuria has disappearedwith time (3,47,50,58).
Despite hematuria, the individuals usually do not have proteinuriaor only minimally so, indicating that the podocyte slit diaphragmis not really affected. The proteinuria develops normally laterthan hematuria, and it is rarely seen in children (3). A significantproportion of adult patients, however, show mild to moderateproteinuria (3,11,17,18,48,59). Conversely, nephrotic-rangeproteinuria is rare even in older patients.
Renal function in children with TBMN is normal (43,49,60), whereasadults have been reported to have low prevalence of renal insufficiency(16,17,26,27,46,47,61). The incidence of renal insufficiencyin these patients might partially reflect the complicated differentialdiagnosis from autosomal or X-linked Alport syndrome or concurrentadditional renal disease. Similarly, rare occurrence of hearingloss in TBMN may as well reflect the difficulties in differentialdiagnosis (18). Also, hypertension has been diagnosed in 11to 31% of adults with TBMN (42,46,47,59,61) but very infrequentlyin pediatric patients (49). The interpretation of these resultsis difficult, but hypertension in patients with TBMN could becoincidental. Generally, the prognosis for the nephropathy intrue TBMN is excellent.
Rogers et al. (11) were the first to associate familial hematuriawith thinning of the GBM. Light microscopy of renal samplesin TBMN shows almost normal glomerular histology with only occasionalmild mesangial cellular proliferation and matrix expansion (62,63).Slight attenuation of the GBM sometimes can be observed by Jonesmethenamine silver or periodic acid-Schiff stains, suggestingGBM thinning. Erythrocytes may be identified in the urinaryspace (62). In approximately 5 to 25% of the cases, focal glomerularsclerosis and tubular fibrosis may be found with aging (26,62),but all histopathologic changes that are observed in light microscopicevaluation are nonspecific. Usually, direct immunofluorescentstaining is negative for Ig and complement, but there sometimesare traces of segmental mesangial positivity for IgM or C3 andrarely IgG or IgA.
Electron microscopy reveals the typical feature of TBMN, i.e.,thinning of the GBM (Figure 1), but it does not distinguishbetween pure TBMN and thin GBM in early stages of Alport syndrome.Normally, the GBM thickness varies with age and gender, andit is also influenced by the method and tissue preparationsused. The GBM thinning in TBMN is uniform, which distinguishesit from patients who have focal thinning process, as is seensometimes in normal children (64), and in patients with minimal-changenephrosis and some other forms of glomerulonephritides (65).In normally fixed kidney samples (e.g., with glutaraldehyde),the GBM appears as a trilaminar structure with a central laminadensa and an inner lamina rara interna and an outer lamina raraexterna. However, in electron microscopic preparations madeusing quick-freezing, the GBM has a uniform appearance (66).According to a general agreement, the GBM thickness is determinedfrom fixed samples as the distance between the outer limitsof the endothelial cell and the base of podocyte foot processcell membranes, which are partially embedded in the GBM (62).As an additional rule, the thickness should be measured onlyin the peripheral capillaries, and multiple measurements shouldbe made over several capillaries of multiple glomeruli (62).
Figure 1. Ultrastructural nature of the glomerular basement membrane in thin basement membrane nephropathy (TBMN). (A) In the normal adult male kidney, one can see a uniformly wide glomerular basement membrane (GBM) located between the fenestrated endothelial cells and the podocyte foot processes. (B) In TBMN, the GBM does not revel any structural abnormalities, but it is characteristically thinned, sometimes having only approximately half of the thickness in a normal kidney (A). Endothelial cells and podocyte foot processes maintain normal morphologic features. Bar = 500 nm. Courtesy: Kjell Hultenby, Karolinska University Hospital, Huddinge, Sweden.
Normal GBM thickness has been estimated in several reports.Osawa et al. (67) compared 587 measurements from normal adultbiopsies and 254 from autopsy samples and showed the averagethickness to be 315 nm with a range of means from 239 to 453nm. Haynes (68) reported the thickness in normal individualsaged between 11 and 26 yr to be 394 nm (range 372 to 632 nm).Using the complicated orthogonal intercept technique (69–71),the mean GBM thickness in female adults was found to be 326nm and that in male adults to be 373 nm. According to thosereports, the thickness increased until a plateau at age 40 yr.According to Vogler et al. (72), the GBM thickness increasesprogressively in children until age 11. At ages 2 d to 1 yr,the thickness is 132 to 208 nm, at ages 1 to 6 yr 208 to 245nm, and at age 6 to 11 yr 244 to 307 nm. As general guidelinesconcerning GBM thickness on the basis of several published results,the mean thickness in male adults is 370 ± 50 nm andin female adults is 320 ± 50 nm (71). In children, theGBM thickness is 150 nm at birth, 200 nm at age 1 yr, and approachesthickness in adults at age 11 yr (72).
A central question, then, is how one should determine what constitutesthin GBM in an individual. The World Health Organization hasproposed a threshold of 250 nm for adults and 180 nm for childrenbetween 2 and 11 yr of age (73). According to Vogler et al.(72), the criteria for TBMN in children vary between <200and <250 nm, and in adults from <200 nm (74) and <250nm (50) or up to <264. This variation in recommendationsis due to difficulties in standardizing the technical methods.This means that the morphologic criteria for thin GBM have tobe evaluated carefully by the pathologist, and one has to takeinto account that the width of the GBM varies according to ageand gender of the patient and also between different laboratoriesas a result of technical differences in sample preparation.Individual criteria should be established for each histologiclaboratory.
In TBMN, the cardinal findings are that the GBM is thinned inmost of the glomerular capillaries and that there is absenceof other significant glomerular pathology. The GBM thicknessvaries in individuals with TBMN (27,74–79); at least 50%of the glomeruli have abnormally thin GBM. Only rare regionsare observed with lamellation or regional thickening, a featuretypically seen in Alport kidneys (1). This may pose a problemin differentiating between TBMN and Alport syndrome, as electronmicroscopic analysis at early stages of Alport syndrome canreveal similar uniform thinning of the GBM (see below for differentialdiagnosis).
Immunohistochemical evaluation of the type IV collagen 3 to5 chains in renal biopsy has become of major importance as amethod to use in differentiating between TBMN and early stagesof Alport syndrome with microscopic hematuria and thin GBM,as these chains usually are either absent or abnormally distributedin Alport syndrome (80,81).
TBMN mainly manifests as an inherited disorder with dominanttransmission affecting approximately one half of successivegenerations (11,28,48). Approximately two thirds of patientswith TBMN have at least one other relative with hematuria (23).The remaining one third of patients may have de novo mutationsor the nonpenetrance in other members of the family (82).
Although TBMN is currently viewed as a common inherited disorderof type IV collagen, the genetic basis of this GBM disease wasnot understood until the late 1990s. The abnormally thin GBMcould be associated with defective structure of the GBM, butthis finding could not be connected with the loss of any GBMproteins, Thus, all of the GBM type IV collagen chains, 1 to5, are present, as are all other known GBM proteins (83,84).
The causes of TBMN started to unravel first through the identificationof type IV collagen genes mutated in Alport syndrome. This kidneydisease, that mainly affects male individuals, is characterizedby early-onset, progressive hematuria that usually developsto ESRD. Type IV collagen is a specific triple-helical structuralcomponent of basement membranes that contain three chains inone individual molecule (85,86). These molecules assemble intoa tightly cross-linked protein meshwork that forms the structuralskeleton of the basement membranes. There are six distinct collagenIV chains, 1 to 6, that are encoded, respectively, by the specificgenes COL4A1 to COL4A6 (Figure 2). The most common form of typeIV collagen molecules contains 1 and 2 chains in a 2:1 ratio(85,86). In some specific basement membranes, such as the GBM,this ubiquitous form of collagen IV is replaced after birthby molecules with the chain composition 3:4:5 (87). This isoformof collagen IV contains more cysteines and is more cross-linkedand resistant to degradation than the ubiquitous 1:1:2 form,and it seems to be essential for the integrity of the postnatalGBM, as well as for some other specialized basement membranesin the inner ear and lens capsule (86). The combination 5:5:6is not present in the GBM, but it is present in the basementmembrane of the Bowman’s capsule, as well as at some otherlocations in the body (88).
Figure 2. Type IV collagen genes, chains, and GBM specific isoforms. (A) The six collagen IV genes (COL4A1 to COL4A6) located pairwise in a head-to-head manner on three different chromosomes generate six different chains that have a globular noncollagenous domain at their C-terminus (B). Three chains form triple-helical molecules that can have different combinations (C) (85,86). (D) Extracellularly, the triple-helical type IV collagen molecules form a network by associating with each other at their ends so that two molecules are cross-linked through their C-terminal globular domain (NC1) and for trimers associated with each other at the N-termini. In the embryonic GBM, the ubiquitous 1:1:2 trimer is the only isoform. After birth, this isoform is gradually replaced by an 3:4:5 isoform (87), which is more cross-linked through disulfide bonds within the collagenous regions (illustrated by black spots) and more resistant to extracellular proteolysis. Defects in the 3:4:5 trimers lead to TBMN or Alport syndrome, depending on the extensiveness of alleles involved (see text). Illustration by Josh Gramling—Gramling Medical Illustration.
Male individuals with progressive X chromosome–linkedAlport syndrome were shown to contain mutations in the COL4A5gene (38), whereas their mothers, carrying one normal allelein addition to the abnormal allele, most often exhibited mildhematuria. Subsequently, the autosomal recessive forms of Alportsyndrome were shown to be due to mutations in the COL4A3 andCOL4A4 genes that are located head to head on chromosome 2 (Figure 2)(41,89). Autosomal Alport syndrome can be caused by homozygousmutations in either of COL4A3 or COL4A4 or by combined heterozygosityfor both. Lemmink et al. (10) noted that some carriers of theautosomal forms of Alport had thin GBM, and this prompted themto analyze the COL4A3 and COL4A4 genes in patients with TBMN.They first showed linkage of the disease with the COL4A3/COL4A4locus and subsequently identified a mutation that leads to asubstitution of glycine to glutamic acid in the collagenousdomain of the COL4A4 gene. Thus, patients with TBMN that islinked to chromosome 2 are heterozygous for mutations in eitherCOL4A3 or COL4A4, and they represent a carrier status for autosomalrecessive Alport syndrome (Figure 3A), in a similar manner asfemale individuals with mutations in one COL4A5 allele are carriersfor X-linked Alport syndrome in male individuals (Figure 3B).Savige et al. (23) showed that up to 36% of TBMN cases associatewith the COL4A3/COL4A4 locus for autosomal recessive Alportsyndrome. More recently, several studies that aimed to identifymutations in the COL4A3 and COL4A4 genes, as well as their commonpromoter region, revealed that heterozygous mutations in thesetwo genes are found in many patients with TBMN (15,23,24,34,42,90–92).The current understanding of the mode of inheritance for autosomalTBMN and autosomal recessive Alport syndrome is depicted inFigure 3A.
Figure 3. Illustration of possible modes of inheritance for autosomal and X-linked forms of TBMN and Alport syndrome (AS). (A) TBMN and autosomal recessive AS in two intermarried families with a mutation (blue color) in COLA3 located on chromosome 2. Half-shaded symbols represent hematuria and heterozygosity state for a mutation in COL4A3 (or COL4A4), and fully shaded symbols represent homozygosity for a mutation or compound heterozygosity for mutations in COL4A3 and COL4A4 resulting in AS. First-generation heterozygotes with TBMN can be considered carriers for recessive AS. Half of the second-generation individuals can be expected to have TBMN. A third-generation offspring of a couple in which both parents have TBMN can be expected to get a child with AS, half of the children being expected to be TBMN patients. However, it has not yet been demonstrated that the offspring of TBMN-affected parents are at risk for developing AS. (B) TBMN simulates nephropathy and AS in a single family in which the mother is heterozygous for a mutation in the X chromosomal COL4A5 gene. Each child has a 25% risk for inheriting the mutant allele. Half-shaded symbols represent heterozygosity and TBMN mimicking disease in females, and fully shaded symbols represent AS (X-AS) in male proband. Illustration by Josh Gramling—Gramling Medical Illustration.
Thus far, 21 COL4A3 and COL4A4 gene mutations have been identifiedin patients with TBMN (82). Mutations in TBMN are scatteredthroughout the COL4A3 and COL4A4 genes without any "hot spots,"similar to what has been observed in the same genes and COL4A5in patients with autosomal recessive and X-linked Alport syndrome,respectively. Most mutations result in single nucleotide substitutionsand lead to missense or nonsense mutations. Many of the mutationslead to a replacement of a glycine in the collagenous domainbut also missense mutations in nonglycine residues of the collagenousdomain. Single amino acid substitutions have been identifiedin the noncollagenous domain, and nonsense and splice site mutationshave also been identified. In addition, six insertion or deletionmutations have been identified. To date, no mutations have beendescribed in the promoter region of COL4A3/COL4A4 genes in TBMN,in contrast to that observed in Alport syndrome.
Heterozygous mutations that are found in patients with TBMNare very similar and, in some cases, identical to those identifiedin patients with autosomal recessive Alport syndrome. So far,only a few studies have attempted to correlate the type of mutationin type IV collagen to the clinical features of TBMN. It isinteresting that Wang et al. (34) reported that the same mutationsin different family members can result in different clinicalfeatures. Autosomal dominant Alport syndrome is also causedby heterozygous mutations in the COL4A3 or COL4A4 gene. As describedabove, the nephropathy in autosomal dominant Alport syndromefollows a much more deleterious course, leading to renal failureand lamellated GBM, in contrast to the symptomless hematuriaobserved in TBMN. It would be crucial to understand the causeof this difference in the clinical outcome of these patientswith heterozygous COL4A3/COL4A4 mutations, but, so far, toofew mutations have been described in autosomal dominant Alportsyndrome and TBMN to distinguish the two on the basis of thegenotype.
The COL4A3 and COL4A4 genes are huge in size; therefore, theidentification of mutations in the genes is difficult. In studiesmade by the Savige group, the mutation detection rate for COL4A3and COL4A4 mutations in patients with TBMN was 11 and 17%, respectively,using single-strand conformation polymorphism (SSCP) (24,34).However, the rate increased to as high as 67% when only individualsfrom families in which TBMN was linked to the COL4A3/COL4A4locus were included. The low detection rate may be due to manyother reasons. First, the use of SSCP instead of direct sequencingof exons lowers the detection rate (93). Thus, sequencing ofall exon regions has been shown to reveal >80% of mutationsin COL4A5 in X-linked Alport syndrome (93). Second, the primersused in the studies were not designed to detect possible splicesite mutations. Furthermore, because of numerous polymorphismsin the genes, some pathogenic alterations in the gene sequencemay be missed and interpreted as nonpathogenic polymorphisms.
Practically all female carriers for X-linked Alport syndromewho have a mutation in one COL4A5 allele exhibit hematuria.In a study of 288 heterozygous female individuals from 329 familieswith X-linked Alport syndrome, 96% had hematuria, and a relativelylarge proportion (30%) had progressive disease that led to chronicrenal failure and ESRD (94). This type of progression is notconsidered typical for TBMN (1). However, the female carriersfor X-linked Alport syndrome do exhibit thinning and thickeningor diffuse thinning of the GBM. Thus, such cases with thin GBMthat mimics TBMN could be considered as TBMN cases. The relationshipof thin GBM and X-linked Alport syndrome is depicted in Figure 3B.
TBMN is a disorder of the trimeric 3:4:5 isoform of type IVcollagen. Therefore, it could be anticipated that a single mutationin any of the alleles for these three genes would lead to asimilar phenotype, as they all affect the same trimeric protein.However, it seems to be a common view in the literature thatonly mutations in COL4A3 or COL4A4 lead to TBMN, as depictedin Figure 3A. It is still possible that X-linked TBMN existswith inheritance, as depicted in Figure 3B. For example, clinicalstudies that were performed before identification of the COL4A5gene indicated the existence of such cases (95,96); similarly,a more recent study by Liapis et al. (97) suggested that a connectionbetween some cases of TBMN and COL4A5 could exist. It is importantto solve this controversy by more extensive sequence analysesof the COL4A5 gene in individuals with TBMN that does not showassociation with chromosome 2.
Many families with TBMN do not show linkage to the COL4A3/COL4A4or COL4A5 loci (98,99). This may be explained by several factors.A high rate of de novo mutations has been shown in the COL4A5gene in X-linked Alport syndrome, and this might be the casein COL4A3 and COL4A4 genes as well (100). Incomplete penetranceof hematuria in heterozygous carriers has also been reported(101), and this can influence linkage analyses. Also, coincidentalhematuria without proteinuria in family member makes it moredifficult to establish linkage. Last, it is possible that someTBMN cases are due to mutations in another, as yet unknown gene.In relation to this, Rana et al. (82) recently studied the linkageof TBMN in nine families who did not show segregation to COL4A3/COL4A4and ruled out linkage to MYH9 (mutations in this gene resultin Alport-like nephropathy) and to genes coding for GBM componentslaminin-5, perlecan, and fibronectin. So far, there are no datashowing any genetic linkage to another loci than COL4A3/COL4A4and COL4A5, supporting the view that TBMN is a disease of theadult form of GBM type IV collagen (3:4:5).
In general, development of autosomal nonprogressive TBMN involvesheterozygous mutations in either COL4A3 or COL4A4, whereas homozygosityor combined heterozygosity of mutations in these genes resultsin autosomal recessive Alport syndrome characterized by deteriorationof the GBM (3,92). Similarly, a TBMN-like phenotype may be causedin a female individual with heterozygosity for a mutation inthe X-chromosomal COL4A5 gene. This could be explained by a"dose effect" whereby absence of one normal allele leads tolower production of the 3:4:5 trimer and thin GBM, whereas theloss of two alleles results in lack of the 3:4:5 trimer andAlport syndrome (35). However, there are reports that a singleheterozygous mutation in COL4A3 or COL4A4 can cause Alport syndromein adult life (15,102,103). This could mean that some mutationsare more serious than others, but it still cannot be excludedyet that in these cases, there is another unknown mutation somewhereelse in the other allele or gene that could lead to absenceof the chain. To date, too few mutations have been identifiedin TBMN and autosomal dominant Alport for making conclusionsabout the differences in pathogenesis.
Differential Diagnosis of TBMN and Alport Syndrome
The characteristic manifestation of TBMN is persistent hematuriaof glomerular origin; therefore, it is important to distinguishthis benign disease from other, superimposing causes of glomerularbleeding. These include IgA nephropathy, postinfectious glomerulonephritis,mesangiocapillary glomerulonephritis, and lupus nephritis. WhereasIgA nephropathy and TBMN may be difficult to distinguish onclinical grounds alone, other forms of glomerulonephritis arefrequently associated with additional clinical features thatrarely are seen in TBMN, such as proteinuria, hypertension,renal impairment, and systemic symptoms.
For initial diagnosis of TBMN, it is critical to be able todistinguish the condition from early stages of Alport syndromethat can yield very similar findings as TBMN. Differential diagnosisof these two is extremely important because of the dramaticallydifferent outcomes of the two disorders. X-linked Alport syndrome,which accounts for approximately 85% of Alport syndrome cases,generally occurs in 1 in 50,000 live births (104), but it canaffect as many as 1 in 5000 male individuals, such as in Utah(38). Typical Alport syndrome findings, such as hearing loss,lenticonus, and severe structural changes in the GBM, developusually first during adolescence. For early diagnosis of Alportsyndrome, it very important to clarify family history. Approximately95% of the female carriers of Alport syndrome have hematuria(105), but they cannot be distinguished from individuals withTBMN (1). However, knowledge about hearing loss, lenticonus,or retinopathy in other relatives can give a hint about X-linkedAlport syndrome.
If the existence of X-linked Alport syndrome is not clear, thenrenal biopsy should be performed. The characteristic uniformthinning of the GBM that is observed in electron microscopyoften confirms the diagnosis of TBMN. However, the importanceof this finding must not be overemphasized, as abnormally thinGBM can also be observed at the early stages of Alport syndrome.Therefore, differential diagnosis from X-linked or autosomalrecessive Alport syndrome should include immunohistochemicalanalysis of the type IV collagen 3 to 5 chains (2,81). In bothforms of Alport syndrome, the expression of all three chainsis usually significantly reduced or absent, whereas in TBMN,the expression is comparable to normal levels (Table 1). Suchanalysis can be performed in many cases on skin biopsies, suchas in X-linked Alport syndrome, in which the 5 chain may beabsent from the epidermal basement membrane, whereas it is notabsent in TBMN (2,81). However, immunohistochemical analysiscan yield in some cases false-negative results, because it hasbeen shown that approximately 20% of autosomal Alport syndromecases and 30% of cases of female carriers for X-linked Alportsyndrome express low or even normal levels (80,102).
Table 1. Expression of collagen IV 3, 4 and 5 chains in normal, TBMN, and AS kidneysa
Genetic analyses can verify the diagnosis, but DNA analysisunfortunately is not generally available. Segregation of thedisease with the COL4A5 locus and sequencing of all of the exonregions can reveal >80% of the mutations in X-linked Alportsyndrome (93), whereas more easily performed methods, such asSSCP, yield only between 37 and 50% of the mutations (106–108).Unfortunately, an assay for screening COL4A5 mutations is currentlynot commercially available. Similar sequencing of the COL4A3and COL4A4 genes is also possible in specialized laboratories.It would be important to be able to provide DNA sequencing ofthe COL4A3, COL4A4, and COL4A5 genes for making diagnosis ofTBMN and Alport syndrome that together form a very large groupof renal disorders. With today’s technologies, such analysismethods should not have to be very costly.
Currently, no clear evidence-based treatment protocols are availablefor TBMN. Although the condition generally has an excellentoutcome and in many cases cannot really be considered a disease,it must be noted that it may not always be benign, and the worseningof the clinical picture has been reported (61,109). It is stilla dilemma for the physician to know whether such cases are infact true TBMN cases or misdiagnosed Alport syndrome. In anycase, patients who receive a diagnosis of TBMN should be monitoredfor the appearance of hypertension, proteinuria, or renal insufficiency,and patients who develop these complications should be treatedaccordingly.
TBMN is one of the most common disorders of the kidney, affectingat least 1% of the population. It seems to be a disease of theadult GBM type IV collagen trimer 3:4:5. Genetic evidence indicatesthat autosomal TBMN is caused by heterozygous mutations in eitherCOL4A3 or COL4A4, whereas homozygous or combined heterozygousmutations in the same genes lead to autosomal recessive Alportsyndrome. Thus, individuals with autosomal TBMN are carriersfor autosomal Alport syndrome. Heterozygosity for mutationsin COL4A5 in female carriers for X-linked Alport syndrome canalso mimic a TBMN condition, although some of those individualswill later develop progressive hematuria (94). It is not clearwhether the individuals with TBMN and female carriers who simulateTBMN and develop progressive disease could have a second mutationin some other of the six alleles that encode the 3:4:5 collagenform. The main clinical problem is to differentiate betweenTBMN and X-linked or autosomal recessive Alport syndrome, asAlport syndrome has severe outcome. Although family historyand electron microscopy of renal biopsies are helpful for diagnosis,immunohistological examination of expression of the type IVcollagen 3 to 5 chains is currently the most informative method.It would be of utmost importance to make sequencing analysesof the COL4A3, COL4A4, and COL4A5 genes available to the clinicas a routine diagnostic method of TBMN and Alport syndrome.
Acknowledgments
We are grateful to Dr. Martin Gregory for critical commentson this manuscript.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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