Collagen type IV ( 3- 4) nephropathy: from isolated haematuria to renal failure

Recent evidence has shown that the COL4A3, COL4A4 and COL4A5 genes are involved in different renal manifestations. Mutations in these collagen type IV genes affect the glomerular basement membrane (GBM) giving rise to a nephropathy whose symptoms range from isolated haematuria to severe renal failure. This disorder has been traditionally considered to be different entities, but the increased knowledge of the molecular basis of this clinical diversity prompted us to agglutinate these entities under the name of ‘collagen type IV nephropathy’. This fact has relevant implications in diagnosis, prognosis and management. Several terms have been used to define the clinical entity consisting of persistent microhaematuria, minimal proteinuria, normal renal function, uniformly thinned GBM and family history of haematuria with an autosomal dominant pattern of inheritance: ‘thin basement membrane disease’, ‘benign persistent haematuria’, ‘benign essential haematuria’ and ‘benign familial haematuria’. The term ‘thin basement membrane disease’ reflects an underlying ultrastructural abnormality common to several renal diseases. On the other hand, the presence of haematuria in the disease is not persistent. Thus the term that best reflects this disorder may be benign familial haematuria (BFH). Thin basement membrane disease (TBMD) is probably the commonest cause of isolated persistent and recurrent haematuria in children and adults and its reported prevalence may range from <1 to 14% depending on the population studied [1]. About two-thirds of TBMD patients have an autosomal dominant familial form of the disease designated as BFH. At least 40% of these families have haematuria that cosegregates with the COL4A3/COL4A4 loci [2,3]. Based on the direct and indirect approach the estimated prevalence of haematuria due to BFH is ∼1% of the population [4,5]. This prevalence implies that this disease is one of the most common conditions affecting the kidney after infections, stones and hypertension. The term benign may not always be appropriate for BFH, as 50% of adults with this disorder have some degree of proteinuria as well as 6% of children. Furthermore, 16% of adults develop proteinuria over 500 mg/day and 17% have hypertension [1]. In addition, some cases of progression towards renal failure have been reported [6,7]. These complications of the disease highly resemble the clinical features of Alport's syndrome (AS). The evidence that GBM from affected young boys or carrier women with X-linked AS are indistinguishable from those in BFH, showing only diffuse thinning of the GBM, makes both diseases look somehow related. As a matter of fact, Hudson et al. [8] in a recent review of AS and Goodpasture's syndrome consider BFH a ‘variant’ of AS. The association of hereditary nephritis and deafness was first recognized by Alport as a definite syndrome in 1927 [9]. The clinical and pathological abnormalities of the AS comprises: persistent haematuria and progressive renal disease, both symptoms being also present in the family history, hearing loss, ocular abnormalities and splitting as well as thinning of the GBM. In rare cases, benign smooth muscle tumours of the oesophagus and female genitalia (leiomyomatosis) occur. However, hearing loss and ocular abnormalities may be absent which complicates the diagnosis of the disease. Mutations in the COL4A5 collagen gene are responsible for XLAS (OMIM 301050) that accounts for 85% of the familial AS cases [10–12]. About 15% of AS families show an autosomal inheritance of the disease, 14% recessive (OMIM 203780) and 1% dominant (OMIM 104200), both caused by mutations in the COL4A3 and COL4A4 collagen genes [13–16]. The clinical features of XLAS constitute the best known of AS phenotypes: boys are much more severely affected than girls, and women are carriers that may eventually reach end-stage renal disease (ESRD) [17]. Autosomal recessive Alport syndrome (ARAS) is characterized by the same severe organ involvement in both boys and girls. This is also true for Autosomal dominant Alport syndrome (ADAS), except for the late development of ESRD. Although few cases of ADAS have been reported it seems more and more feasible that it may constitute the severe phenotype of the traditionally named BFH [18]. Basement membranes are assembled through an interweaving of type IV collagen with laminins, nidogen and sulphated proteoglycans. COL4A1 to COL4A6 are the genes encoding the six existing α (IV) chains which are expressed in different membranes at different stages of embryonic development. These chains form three sets of triple helical molecules called protomers, which consist of: α1,α1,α2(IV); α3,α4,α5(IV); α5,α5,α6(IV) [19]. The first set is only found in the embryo and is gradually replaced by the other two protomers. This developmental switch of molecules is a critical step in the maturation of the kidney. Mutations in the COL4A3, COL4A4 or COL4A5 genes produce a post-translational defect in protomer assembly that prevents the correct structure of collagen type IV network (Figure 1). The GBM is then exposed to proteases and oxidants and does not have the protection of a resistant collagen IV network. Therefore, over time, patients with a defective collagen type IV network become more sensitive to selective basement membrane proteolysis, and the GBM becomes thicker, splits and ultimately deteriorates to the point of allowing blood and proteins to come through [20]. Presumably, slightly defective collagen type IV assembly only causes thinning of the GBM. Genotype–phenotype correlation in COL4A3, COL4A4 and COL4A5 mutations. XLAS, X-linked Alport syndrome; ARAS, autosomal recessive Alport syndrome; ESRD, end-stage renal disease. Considering the GBM similarities between BFH and AS, it seemed reasonable to assume that these diseases could be the extremes of a wide phenotypic spectrum of different molecular defects within the same gene(s). Lemmink et al. [21] first confirmed this hypothesis by demonstrating linkage to 2q35-37 (COL4A3 and COL4A4) in a large family affected with autosomal recessive AS and BFH. BFH patients were found to be heterozygous for a G897E substitution in the COL4A4 gene. The index case had a renal biopsy compatible with AS and had inherited the mutation from his father, but the mother also had haematuria. The hypothesis was that the mother transmitted a second unknown mutation within the COL4A4 gene and thus the patient had both copies of the gene mutated and developed AS. Some mutations within the COL4A4 and COL4A3 genes have been described in families with ARAS where the heterozygotes present haematuria [2,3,21–24] and also mutations in these genes previously found in ARAS have been described in BFH [23]. These findings have serious implications for genetic counselling, as the offspring of two parents with familial haematuria may be at risk of developing AS. However, none of the families with BFH are linked to the COL4A3/COL4A4 locus [2,25,26], nor do all carriers of autosomal AS have haematuria. We must bear in mind that haematuria may have an incomplete penetrance thus, some families apparently not linked to the COL4A3/COL4A4 loci may eventually have a mutation in these genes [18,27]. Also, we must remember that there may be ‘de novo’ mutations and why not, mutations in other genes may be implicated in BFH. Compound heterozygotes with one mutation in the COL4A3 and another in the COL4A4 have only microhaematuria, confirming the suspicion that both alleles of either COL4A3 or COL4A4 must be mutated to cause AS [27]. Yet, the most outstanding fact is that mutations in either COL4A3 or COL4A4 have been found in the heterozygous state, the so-called ADAS [15,24,27,28]. In all these cases renal failure develops late in life and in some of them it is not even present. Moreover, this disease may remain underdiagnosed because renal failure occurs in adulthood and may be indistinguishable from an advanced glomerulopathy. Curiously, some cases of evolution towards heavy proteinuria and severe renal failure have been described in BFH [6,7], demonstrating that BFH and ADAS in fact belong to a continuous spectrum of graded severity caused by mutations in the COL4A3 and COL4A4 genes. The different outcome of mutations within these genes may be explained by the proteomic consequences of the mutation (molecular heterogeneity) or perhaps, by the involvement of other structural proteins of the glomerular podocyte or slit diaphragm, such as nephrin, podocin and β-actin which may interact with type IV collagen and affect the GBM integrity [29]. Mutation screening is not currently available for performing molecular diagnosis of collagen type IV (α3, α4) nephropathy. This is due to the large size of these genes and the high number of polymorphisms, which make the usual techniques relatively insensitive (60% of mutation detection) [2]. Mutations in the COL4A3, COL4A4 and COL4A5 genes produce an alteration of the GBM structure. Depending on the age, sex, type of mutation and number of genes mutated the resulting phenotype may range from a thinned GBM to GMB thickening, lamellation and splitting, which in clinical terms goes from isolated microhaematuria to full blown AS. The new term ‘collagen type IV (α3–α4) nephropathy’ permits us to group the entities previously known as BFH, ADAS and ARAS carriers into a unique clinical and molecular concept for an improved disease comprehension. As our knowledge of genomics and proteomics of the disease improves, we hope to be able to establish a prognosis and eventually to design a treatment to prevent the deterioration of GBM structure and function in this disorder. This work was supported by a grant from the Spanish Ministry of Health (REDEMETH). Conflict of interest statement. None declared.