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Collagen IV is a class of extracellular matrix protein found ubiquitously in basement membranes of various organs, including kidneys [1]. Six collagen IV α chains, α1(IV) to α6(IV), encoded by COL4A1 to COL4A6 genes, respectively, assemble into three different heterotrimers: collagen α1α1α2(IV), α3α4α5(IV), and α5α5α6(IV). Collagen α3α4α5(IV) is the major component of the mature glomerular basement membrane (GBM), though there is a thin layer of collagen α1α1α2(IV) at the GBM's endothelial aspect (Fig. 1a, b). Pathogenic variants in COL4A3, COL4A4, or COL4A5 leading to absence or disruption of the GBM collagen α3α4α5(IV) network (Figs. 1 and 2) cause Alport syndrome (AS) [2,3]; thus, these will be referred to as Alport genes in this article.
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FIGURE 1: Schematic diagram of glomerular basement membrane (GBM) collagen IV in health and disease associated with different types of Alport gene variants. (a) The GBM is a network of extracellular matrix proteins flanked by endothelial cells and podocyte foot processes. (b) Normal GBM consists predominantly of a thick layer of collagen α3α4α5(IV) (blue) secreted by podocytes. Collagen α1α1α2(IV) (red), secreted by endothelial cells, appears as a thin layer at the endothelial aspect of the GBM. (c, d) In classic severe Alport syndrome (AS), (c) truncating variants result in no deposition of collagen α3α4α5(IV) in the GBM with a compensatory increase of collagen α1α1α2(IV), while (d) nontruncating variants result in deposition of defective collagen α3α4α5(IV) (yellow). (e, g) As for COL4A3 or A4 heterozygotes, (e) in cases of truncating variants, the wild-type allele contributes to expression of approximately 50% of intact collagen α3α4α5(IV) to the GBM, while (g) in cases of nontruncating variants, deposition of collagen α3α4α5(IV) derived from both alleles results in a mixture of 50% intact and 50% defective collagen α3α4α5(IV). (f) In digenic AS due to heterozygous variants in both COL4A3 and COL4A4, truncating variants in both genes result in a decrease in GBM deposition of intact collagen α3α4α5(IV) to 25% of normal, while (h) nontruncating variants in both genes result in a GBM network of 25% intact and 75% defective collagen α3α4α5(IV). Note that these percentages are only accurate if all nontruncated defective collagen IV trimers are secreted into the GBM, which is not always the case.
FIGURE 2: Schematic diagram of glomerular basement membrane (GBM) collagen IV in females with heterozygous X-linked Alport syndrome (AS). Unlike autosomal variants, heterozygous X-linked COL4A5 variants cause mosaic deposition of collagen α3α4α5(IV) in the GBM depending on which allele (wild-type or mutant) is active in the overlying podocytes after X inactivation. For truncating variants, the affected region of the GBM (covered by red podocytes) completely loses collagen α3α4α5(IV) with a compensatory increase of collagen α1α1α2(IV). For nontruncating variants, the affected region of the GBM (covered by yellow podocytes) can deposit only defective collagen α3α4α5(IV). The unaffected regions covered by podocytes with wild-type alleles show normal GBM collagen α3α4α5(IV). Transition zones are depicted where podocytes expressing the wild-type COL4A5 allele interdigitate with podocytes expressing a mutant allele.
The “classic” AS presentation is characterized by childhood-onset hematuria, later onset proteinuria, progressive decline in kidney function, and kidney failure (KF) in adolescence or young adulthood, along with sensorineural hearing loss, and eye abnormalities [4,5]. Because COL4A5 is X-linked, male patients with X-linked Alport syndrome (XLAS) typically exhibit more severe symptoms than females with XLAS. In contrast, COL4A3 and COL4A4 are on chromosome 2, and variants cause the more rare autosomal recessive Alport syndrome (ARAS), which affects males and females equally [1]. Heterozygous COL4A3 and COL4A4 variants have been linked to thin basement membrane nephropathy (TBMN), also called benign familial hematuria (BFH) [6]. However, these are now considered disfavored terms for less severe kidney diseases within the Alport spectrum, and in some cases have been classified as autosomal forms of AS [7]. Moreover, a variable degree of GBM thinning is in some cases the only early pathologic finding in diseases within the Alport spectrum and is quite common, making “thinning of GBM” a nonspecific finding (Table 1). Therefore, it has been suggested that “thin basement membrane lesion” be used as a term to describe the pathology rather than to justify a diagnosis of TBMN as a specific disease entity [7].
Table 1 - Clinical groups and the associated Alport gene variants Groups Alport gene status Clinical features Biopsy findings Kidney outcomes 1. Classic severe AS (males with XLAS, ARAS) COL4A5 -/YaDigenic AS in males with COL4A5 −/Y plus COL4A3 or COL4A4 +/− have classic severe phenotypes similar to males with XLAS. Addition of pathogenic COL4A3 or A4 variants does not worsen the phenotypes.ADAS, autosomal dominant Alport syndrome; ARAS, autosomal recessive Alport syndrome; AS, Alport syndrome; KF, kidney failure; SNHL, sensorineural hearing loss; XLAS, X-linked Alport syndrome; y, years.
With the increased utilization of molecular genetic testing in clinical practice, pathogenic variants in Alport genes have been increasingly reported in patients with diverse clinical presentations, including a more proteinuria-predominant phenotype (nephrotic-range proteinuria or steroid-resistant nephrotic syndrome) [8,9], kidney failure of unknown etiology [10], familial immunoglobulin A (IgA) nephropathy with thin basement membrane [11], and renal cysts in whom polycystic kidney disease has been ruled out [12,13]. Several studies also consistently reported that pathogenic Alport gene variants are the most frequently found genetic abnormalities in adult-onset familial nephrosis with focal segmental glomerulosclerosis (FSGS) lesions [8,9].
Detection of Alport gene variants among patients with diverse clinical presentations challenges the traditional classification of AS/TBMN/BFH/ADAS, and newer terms such as “spectrum of Alport syndrome”, “Alport-related nephropathy”, “collagen IV related renal disease”, and “collagen IV associated nephropathy” have been used in the literature to denote the kidney disease states linked to pathogenic variants in COL4A3/A4/A5. This review aims to summarize the different clinical manifestations in this disease spectrum and the challenges in categorizing patients due to overlapping and inconsistent presentations and the complex genetics involved. We also put forth the term “Alport kidney disease” to describe nonsyndromic kidney disease resulting from pathogenic variants in the Alport genes. Importantly, retention of “Alport” distinguishes COL4A3/A4/A5 nephropathies from the much rarer ones caused by variants in COL4A1 and COL4A2 (Gould syndrome) [14]. We hope this term will be considered for adoption by relevant stakeholders, including patients, clinicians, geneticists, and scientists.
CLINICAL SPECTRUM OF KIDNEY DISEASES ASSOCIATED WITH ALPORT GENE VARIANTSBased on the diverse kidney phenotypes described above, we propose that the spectrum of kidney diseases associated with pathogenic Alport gene variants be categorized into four groups: classic severe AS (male hemizygous XLAS and ARAS of either sex); mild to moderate AS (female heterozygous XLAS, ADAS, and digenic AS); Alport kidney disease with predominant proteinuria, steroid-resistant nephrotic syndrome, and FSGS lesions (AD); and hematuric Alport kidney disease, a mild condition that portrays the clinical picture of thin basement membrane lesions with very minimal risk of KF (AD) (Table 1). We note that not every patient with a pathogenic variant in an Alport gene will fit perfectly in a specific group, as many factors can impact disease manifestation. Moreover, disease classification can be dynamic, as patients initially placed into a less severe group may develop severe/high-risk features, emphasizing the importance of follow-up for patients in all groups, as previously suggested [7].
GROUP 1: CLASSIC SEVERE ALPORT SYNDROMEThis category encompasses hemizygous males with XLAS and males or females with ARAS. Rare females with biallelic pathogenic COL4A5 variants would also fit in this category [15]. These patients generally exhibit a 100% penetrance of hematuria since infancy. Albuminuria develops later and is an indicator of kidney disease progression; KF is inevitable. In males with XLAS, 70% reach kidney failure by the age of 30 years, and 90% at 40 years [16,17]. Electron microscopy of kidney biopsies usually shows diffusely thinned GBMs at early stages, and GBM lamellation and characteristic basket-weave at later stages [18]. Extrarenal features due to lack or dysfunction of collagen α3α4α5(IV) in cochlea and lens/retina/cornea basement membranes are common but not always present. Some hearing loss occurs in 90% of patients before the age of 40 [16]. Fleck retinopathy is common and can aid in the diagnosis of AS [19,20]. Peripheral fleck retinopathy is present in most cases of XLAS and ARAS, whereas central fleck retinopathy is present in 50–60% of patients with XLAS and ARAS. Both central fleck retinopathy and anterior lenticonus are associated with an increased risk of early-onset kidney failure [20].
Genotype–phenotype correlations in this category of patients are relatively straightforward. According to the Leiden Open Variation Database (LOVD; https://www.lovd.nl), the mean age at kidney failure was 25.1 ± 10.6 years overall in males with XLAS, 20.4 ± 5.0 years in those with nonsense variants, 21.1 ± 6.8 years in those with deletions, 25.2 ± 10.7 years in those with canonical splice site variants, 28.45 ± 12.4 years in those with collagenous-domain Gly substitutions, and 40.7 ± 17.6 years in those with non-Gly substitutions [21▪].
The molecular defect that best explains the most severe AS phenotypes is the lack of the collagen α3α4α5(IV) network in the GBM. Males with hemizygous truncating COL4A5 variants or patients with homozygous/compound heterozygous truncating COL4A3 or COL4A4 variants cannot produce collagen α3α4α5(IV) heterotrimers, resulting in their complete absence from the GBM (Fig. 1c) and the most severe presentations. In contrast, patients with positive collagen α3α4α5(IV) staining by immunohistochemistry (Fig. 1d), most of whom should have missense variants (often glycine substitutions), show a lower degree of albuminuria and older age at KF [22,23]. This strongly suggests a correlation between genotype and the presence or absence of collagen α3α4α5(IV) in the GBM, even if the collagen IV is abnormal.
GROUP 2: MILD-TO-MODERATE ALPORT SYNDROMEThis category includes a group of genetically heterogeneous patients, but they all share milder and more slowly progressive AS phenotypes, usually reaching KF after age 40. Extra-renal features are less common than in severe classic AS or are absent. Patients that fall into this category are females with heterozygous COL4A5 variants, patients with heterozygous COL4A3 or COL4A4 variants who show symptoms of AS (ADAS), and patients with digenic AS.
Females with heterozygous X-linked Alport syndromeIn females, cells undergo X-chromosome inactivation during development to equalize the expression of X-linked genes with males. For COL4A5+/− females, this process creates a mosaic state in which segments of the GBM have either normal or absent/aberrant collagen α3α4α5(IV), depending on the nature of the variant (Fig. 2). GBM mosaicism underlies the variable and usually milder phenotypes, and such females were once considered “just carriers” of XLAS. However, they are now included in the AS spectrum because many develop classic AS phenotypes, though with a slower rate of kidney function loss; KF is not inevitable [24▪▪,25].
Nearly all females with XLAS have persistent microscopic hematuria from infancy, and the presence of albuminuria indicates risk of progression to KF [26], albeit at a much slower rate than males with XLAS. From the large European cohort of 506 female XLAS patients from 195 families and another cohort of 275 female patients from 179 families in Japan, only 12–15% developed KF before the age of 40 years, and 30–40% before the age of 60 years [16,27]. A more recent study of 86 female patients with XLAS from Korea estimated the median age at KF to be 50.2 (39.0–61.5) years [28▪]. Hearing loss occurred in 5.5–28%, usually developing by middle age. The presence of fleck retinopathy, although only observed in ∼25–30% of patients, is helpful for diagnosis; anterior lenticonus has not been reported in females with XLAS [20,25]. Kidney biopsy is performed less in females because of equivocal diagnostic yield and procedural risks. The GBM may show thinning with or without lamellation. Finally, recent data indicate that there are genotype–phenotype correlations in females with XLAS [28▪,29] that are consistent with findings described above for the patients in Group 1.
Autosomal dominant Alport syndromeThe features of ADAS, caused by heterozygous variants in COL4A3 or COL4A4, are similar to those of XLAS and ARAS, but extrarenal manifestations are less prevalent, and KF is delayed and is not inevitable. A recent systematic review of 777 patients with ADAS reported in 48 publications showed hearing loss and eye abnormalities in 16% and 3% of patients, respectively [30]. A subsequent study of 240 individuals from 78 families reported hearing loss and ocular abnormalities in only 8% and 1%, respectively [31]. Collectively, these frequencies are far less than in classic severe AS. These two studies reported that 24–29% of patients developed KF, at a median age of 53–67 years [30,31].
It is important to note here that for individuals carrying a heterozygous pathogenic COL4A3 or COL4A4 variant, which is estimated to be ∼1% of the population [32], very few will develop symptoms consistent with an AS diagnosis. This is discussed in detail below under Group 4. But of relevance here, two independent studies of patients with heterozygous pathogenic variants in COL4A3[33▪▪] or in either COL4A3 or COL4A4[34▪▪] found that nontruncating variants (mainly Gly substitution missense variants) caused more severe symptoms, such as higher degree and/or earlier hematuria and proteinuria, lower GFR, and higher rates of KF vs. truncating or in-frame deletion variants. This suggests a dominant negative effect in which defective collagen IV chains disrupt the integrity of the intact ones (Fig. 1g). This is opposite to the situation for XLAS and ARAS, in which truncating variants cause the more severe disease.
Digenic Alport syndromeVariants in more than one Alport gene have been found in a very small number of patients with a clinical diagnosis within the spectrum of AS. The possible combinations include patients carrying COL4A3 plus COL4A4 variants, and either a COL4A3 or a COL4A4 variant plus a COL4A5 variant. The three patterns differ in modes of inheritance and clinical courses depending on the involvement of COL4A5, the nature of the pathogenic variants, and other factors [35].
The presence of an additional variant may or may not affect phenotypes depending on whether the collagen α3α4α5(IV) network can be worsened further. In the case of severe AS (Group 1) with collagen α3α4α5(IV) completely absent from the GBM, an additional Alport gene variant cannot worsen the phenotype. However, for patients who have a heterozygous COL4A3 or COL4A4 variant and thus can still deposit normal collagen α3α4α5(IV) into the GBM, an additional variant in another COL4A gene will increase the percentage of defective collagen α3α4α5(IV) to 75% from 50% and worsen the phenotype (Fig. 1h). Digenic patients show phenotypes intermediate between ADAS and ARAS in terms of age at KF, and hearing loss was more frequent than in ADAS but less frequent than in ARAS [36▪].
GROUP 3: ALPORT KIDNEY DISEASE WITH PREDOMINANT PROTEINURIA, STEROID-RESISTANT NEPHROTIC SYNDROME, AND FOCAL SEGMENTAL GLOMERULOSCLEROSIS LESIONSDeltas et al. were the first to demonstrate a link between proteinuria with FSGS lesions and heterozygous variants in COL4A3 or COL4A4[37,38], and they have studied additional families that support this link [39–41]. Several other independent sequencing initiatives have shown that about 10% of patients with FSGS lesions and heavy proteinuria have variants in Alport genes, primarily heterozygous variants in COL4A3 and COL4A4[8–10,42,43]. These patients do not have ocular abnormalities and only rarely experience hearing loss, usually later in life, making it difficult for physicians to order genetic testing for Alport gene variants. Nevertheless, they carry a high risk of kidney disease progression, reaching KF at 40–65 years, later than classic severe AS [8,9].
In most of these patients, electron microscopy only showed segmental thinning or splitting of GBM [9,42], which is not characteristic of AS; though FSGS lesions are expected to develop late in the course of classic AS, they are associated with GBM basket-weave thickening and tubulointerstitial scarring. This suggests the possibility that some Alport gene variants may cause the proteinuria-predominant phenotype associated with FSGS lesions [44]. Secreted solely by podocytes, the production of aberrant collagen α3α4α5(IV) may affect podocyte homeostasis, resulting in podocyte damage, proteinuria, and development of FSGS lesions [45]. Knockin of a human COL4A3 variant that expresses misfolded collagen α3(IV) chains into mice increased the unfolded protein response pathway, which can be linked to podocyte endoplasmic reticulum stress [46]. This may explain why heterozygous substitution variants are associated with more severe proteinuria than heterozygous truncating variants [33▪▪] and why not all patients harboring heterozygous COL4A3 or COL4A4 variants have proteinuria-predominant phenotypes.
Some authorities suggest proteinuria and FSGS lesions that occur in this subgroup of patients are results of other genetic modifiers that could have been overlooked [47,48▪]. However, most cohorts reporting the link between Alport gene variants and FSGS lesions also examined other genes implicated in nephrotic syndrome but could not detect any variants [8,9].
GROUP 4: HEMATURIC ALPORT KIDNEY DISEASEThis last group covers a subgroup of individuals carrying heterozygous pathogenic variants in COL4A3 or COL4A4, estimated to be around 1% of the population, ∼70% of whom have hematuria [32]. This group encompasses the largest proportion of the whole disease spectrum. Unlike patients in groups 2 and 3, most individuals in this group have only isolated microscopic hematuria associated with thin GBM without any high-risk features (such as proteinuria), putting them at a slightly increased risk of developing KF late in life. These are the patients whom Kashtan et al.[7] previously suggested should be made cognizant of this risk and to be proactive about monitoring and treatment according to expert recommendations [49,50]. A subset of these individuals will be parents or siblings of patients with ARAS and will be aware of the importance of maintaining kidney health. Although this group of patients has a benign prognosis, as what was assumed for those with thin basement membrane lesions, it should be emphasized that their underlying Alport gene status may be similar to ADAS. The type of variant or other modifying factors such as hypertension, obesity, and other comorbidities could be what differentiate these patients from ADAS, but this remains uncertain. Moreover, polygenic risk factors can impact the chances that COL4A3 or COL4A4 heterozygous individuals develop severe phenotypes [51▪▪]. In any event, some individuals initially placed into Group 4 will develop symptoms over the course of decades and will need to be recategorized.
CONCLUSIONThe genetic and clinical complexities of Alport syndrome and the related Alport kidney diseases make the classification of patients with less severe manifestations difficult and subjective. These patients are much more numerous than those with classic severe AS, so there is an urgency to ensure that they receive appropriate attention and care from nephrologists even if the risk of KF is low. This led the Alport Syndrome Classification Working Group to suggest the diagnosis of autosomal AS for any individuals with heterozygous COL4A3 or COL4A4 variants [7], including those with isolated thin basement membrane lesions who might never reach KF. Although the working group recommended classifying patients based on mode of inheritance, in this review we proposed a more detailed patient classification across the disease spectrum by severity of AS phenotypes, from the classic severe AS (XLAS in males and ARAS), in which there is no intact collagen α3α4α5(IV) in the GBM, to hematuric Alport kidney disease, the most favorable prognosis with only a slightly increased risk of KF over the general population. We also emphasized those patients with a proteinuria-predominant Alport kidney disease presentation (Group 3) who might be diagnosed as FSGS and given unnecessary immunosuppressive therapy. With the growing evidence for genotype–phenotype correlations, the phenotype-based classification somewhat follows the underlying genetic abnormalities. Establishing a solid link between GBM collagen IV defects (Figs. 1 and 2) and clinical presentation will lead to better patient classification, risk stratification, and improved patient care.
AcknowledgementsWe thank André Weinstock (Alport Syndrome Foundation), Susie Gear (Alport UK), Rachel Lennon (University of Manchester, UK), and Judy Savige (University of Melbourne) for helpful discussions that led to the descriptor “Alport Kidney Diseases”.
Financial support and sponsorshipJ.H.M. is supported by NIH R01DK128660 and U54DK137332.
Conflicts of interestJ.H.M. is a member of the Alport Syndrome Foundation's Scientific Advisory Research Network, has served as a consultant to Bayer AG and Eloxx Pharmaceuticals, and has received funding for research from Chinook Therapeutics, LTI Therapeutics, and Keros Therapeutics. P.P. has no conflict of interest to declare.
REFERENCES AND RECOMMENDED READINGPapers of particular interest, published within the annual period of review, have been highlighted as:
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