Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)

INTRODUCTION — Alport syndrome (also referred to as hereditary nephritis) is an inherited progressive form of glomerular disease that is often associated with sensorineural hearing loss and ocular abnormalities [1]. Alport syndrome is a primary basement membrane disorder arising from pathogenic variants in genes encoding several members of the collagen IV protein family.

The clinical manifestations, diagnosis, and treatment of Alport syndrome will be reviewed here. The pathogenesis, genetics, and pathology of Alport syndrome are discussed separately. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)

GENETICS — Alport syndrome is a genetically heterogeneous disease that results from disease-causing variants in genes encoding the alpha-3, alpha-4, and alpha-5 chains of collagen IV [1]. These collagen IV alpha chains are normally located in various basement membranes of the kidney, cochlea, and eye. Abnormalities in these chains result in defective basement membranes at these sites, leading to the clinical features of this disorder (ie, progressive glomerular disease, sensorineural hearing loss, and ocular abnormalities). (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Genetics' and 'Clinical manifestations and course' below.)

Transmission of Alport syndrome can be X-linked, autosomal recessive, autosomal dominant, or, in rare cases, digenic. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Genetics'.)

●X-linked transmission accounts for the majority of affected patients who exhibit progressive kidney disease and hearing loss and arises from variants in the COL4A5 gene on the X chromosome.

●Autosomal recessive disease accounts for 10 to 15 percent of patients and arises from genetic defects in either the COL4A3 or COL4A4 genes.

●Autosomal dominant disease appears to account for 20 to 30 percent of patients with progressive kidney disease and arises from heterozygous variants in the COL4A3 or COL4A4 genes.

●Some families exhibit digenic inheritance due to transmission of variants in two of the three genes (COL4A3, COL4A4, COL4A5).

EPIDEMIOLOGY — Alport syndrome has been reported in hundreds of unrelated kindreds that represent all geographic and ethnic groups. Although the overall incidence in the general population is unknown, data from the United States demonstrates Alport syndrome accounts for 3 percent of children with kidney failure (previously referred to as end-stage kidney disease) and 0.2 percent of adults with kidney failure [2].

Among children undergoing kidney biopsy, the incidence of Alport syndrome has varied from 1 to 12 percent depending on the indication for biopsy [2-5].

The gene frequency of Alport syndrome in the United States has been estimated at 1:5000 to 10,000, suggesting that there are approximately 30,000 to 60,000 affected individuals in the United States [6]. In Sweden, the risk of X-linked Alport syndrome was estimated to be 1 in every 17,000 live male births [7]. More recent studies have provided estimates of the prevalence of pathogenic variants in the three collagen type IV genes using sequencing databases: COL4A5, 1 in 2320 individuals; heterozygous COL4A3 and COL4A4 variants, 1 in 106 individuals; compound heterozygous variants in COL4A3 and COL4A4, 1 in 88,866 individuals [8].

CLINICAL MANIFESTATIONS AND COURSE — The classical presentation of Alport syndrome is based on clinical manifestations of affected males with X-linked disease. These features include glomerular disease that progresses to kidney failure, ocular abnormalities (eg, anterior lenticonus), sensorineural hearing loss, family history of male relatives with hematuria associated with kidney failure and deafness, and female relatives with hematuria.

Clinical presentation and course in patients with autosomal recessive disease are similar to those with X-linked disease. Patients with autosomal dominant disease generally exhibit more gradual loss of kidney function [9,10]. Sensorineural hearing loss and ocular anomalies are common in the X-linked and autosomal recessive forms of Alport syndrome but are unusual in patients with autosomal dominant disease. (See 'Genetics' above.)

Kidney manifestations — The initial kidney manifestation of Alport syndrome is asymptomatic persistent microscopic hematuria, which is present in early childhood in affected patients. Since screening urinalysis is seldom performed in routine pediatric primary care, microscopic hematuria may not be detected unless the patient is screened because of an affected family member or found as an incidental finding for another issue (see "Evaluation of microscopic hematuria in children", section on 'Asymptomatic isolated microscopic hematuria'). Gross hematuria may be the initial presenting finding and often occurs after an upper respiratory infection [11]. However, recurrent episodes of gross hematuria are not uncommon, especially during childhood. Males without hematuria by the age of 10 years are unlikely to have Alport syndrome [2]. Patients with Alport syndrome have normal serum complement component 3 (C3) levels.

In early childhood, the serum creatinine and blood pressure are normal. Over time, proteinuria, hypertension, and progressive kidney insufficiency develop. Kidney failure usually occurs between the ages of 16 and 35 years in patients with X-linked or autosomal recessive disease. In some families, the course is more indolent with kidney failure being delayed until age 45 to 70, especially in those with autosomal dominant Alport syndrome.

In females with X-linked Alport syndrome, recurrent episodes of gross hematuria, proteinuria, hearing loss, and diffuse glomerular basement membrane (GBM) thickening and lamellation are associated with more severe kidney dysfunction and kidney failure at an earlier age [12].

Hearing loss — Bilateral sensorineural hearing loss is common in patients with X-linked and autosomal recessive Alport syndrome [13,14]. Hearing loss typically begins in the high frequency range and progresses over time to frequencies in the range of conversational speech. One study of families with X-linked disease reported that audiologic testing detected hearing loss in 85 percent of affected males and 18 percent of female heterozygotes by 15 years of age [11]. In general, the rate of hearing loss is similar to the progression of kidney insufficiency, although complete hearing loss that is unresponsive to hearing aids is unusual.

Ocular manifestations — Several ocular defects involving the lens, retina, and cornea have been reported in patients with Alport syndrome [15,16].

●Lens – Anterior lenticonus is a regular conical protrusion on the anterior aspect of the lens due to thinning of the lens capsule (figure 1). It occurs in 20 to 30 percent of males with X-linked Alport syndrome and is pathognomonic of the disease. Lenticonus can be complicated by the presence of subcapsular cataracts, which may lead to loss of visual acuity. (See "Cataract in children".)

●Retina – Retinal changes are usually asymptomatic, and, when there is anterior lenticonus, they are always present [17]. The changes consist of bilateral white or yellow granulations that are superficially located in the retina surrounding the foveal area (also referred to as dot and fleck or fleck retinopathy) [18]. These findings are also specific for Alport syndrome. Some patients have developed macular holes with impaired vision [19].

●Cornea – Corneal changes in patients with Alport syndrome can include posterior polymorphous dystrophy and recurrent corneal erosion, which can cause severe ocular pain.

Leiomyomatosis — Leiomyomas are benign tumors characterized by visceral smooth muscle overgrowth within the respiratory, gastrointestinal, and female reproductive tracts. They are found in 2 to 5 percent of patients with X-linked Alport syndrome who have chromosomal microdeletion at the 5' ends of COL4A5, which extend into the adjacent COL4A6 gene [20,21].

Arterial disease — Aneurysms of the thoracic and abdominal aorta have been reported in relatively young male patients, as well as a single case of intracranial aneurysm [22-24].

PHENOTYPE-GENOTYPE CORRELATION — The tempo of progressive kidney dysfunction depends, at least in part, on the underlying variant.

●X-linked Alport syndrome – For individuals with X-linked Alport syndrome, the presence of truncating variants (such as deletions and nonsense mutations) is associated with more rapidly progressive disease (both kidney and extrarenal) compared with missense mutations [2,25-29]. This was illustrated in the following reviews of families with X-linked Alport syndrome that demonstrated the correlation between kidney failure and types of variants in the COL4A5 gene.

•In the first study of 195 European families, the risk of kidney failure by 30 years of age for male patients with missense variants; splice-site variants; and large deletion, nonsense, or frameshift variants was 50, 70, and 90 percent, respectively [28]. Large rearrangements of the COL4A5 gene or any variants that shift the reading frame of the gene were also associated with earlier onset of hearing loss and a higher incidence of anterior lenticonus [28].

•In the second study of 175 families from the United States, the average age of onset for kidney failure for male patients with missense, splice-site, and truncating variants was 37, 28, and 25 years of age, respectively [29]. Variants located closer to the 5' end of the gene were associated with an earlier onset of kidney failure and an increased risk of ocular changes and hearing loss than those located closer to the 3' end. Patients with splice-site or truncating variants were also more likely to have ocular abnormalities and hearing loss.

●Heterozygous females with X-linked disease – Females with X-linked Alport syndrome are heterozygous for variants in the COL4A5 gene. They have a range of clinical findings due to lyonization, by which only one X chromosome is active per cell. As a result, approximately one-half of their cells will express the mutant COL4A5 gene and the remaining cells will express the normal COL4A5 gene, leading to a variable phenotype that is generally less severe than in affected males.

This was shown in a study of the natural history of female heterozygotes with proven COL4A5 mutations [30]. Among female heterozygotes followed in 195 affected families, the incidence of kidney failure before age 40 was 12 percent, compared with 90 percent in affected males [28]. With increasing age, there was an increased risk of progressive kidney disease, with a 30 percent probability of developing kidney failure by age 60 in these females. However, this may be an overestimate since approximately one-third of the females, most likely less severely affected, were lost to follow-up. There was variation in phenotypes among family members with the same genotype, most likely due to the variability of gene expression due to lyonization.

Risk factors for chronic kidney disease in female heterozygotes include episodic gross hematuria in childhood, sensorineural deafness, proteinuria, and presence of the characteristic lamellation of the basement membrane (GBM) associated with Alport syndrome on kidney biopsy [30-33]. By comparison, female heterozygotes with only asymptomatic hematuria by the age of 30 to 40 years have a relatively small risk of developing kidney failure.

●Autosomal recessive Alport syndrome – Individuals with autosomal recessive Alport syndrome due to biallelic pathogenic variants in COL4A3 and/or COL4A4 have similar disease severity to males with X-linked disease. In a systematic review of a referral population, nearly all such individuals had hematuria and proteinuria and 60 percent had end-stage kidney disease [34].

●Autosomal dominant disease – Individuals with autosomal dominant Alport syndrome due to a heterozygous COL4A3 or COL4A4 variant have a highly variable phenotype. In a referral population, clinical manifestations included hematuria (95 percent), proteinuria (46 percent), chronic kidney disease (29 percent), end-stage kidney disease (15 percent), hearing loss (16 percent), and ocular manifestations (3 percent) [34]. However, a population-based study reported a much higher proportion of individuals with asymptomatic or minimally symptomatic disease [35]. Most participants had not been diagnosed with Alport syndrome, and only 6 percent had end-stage kidney disease.

●Other – A contiguous gene syndrome consisting of X-linked Alport syndrome, midface hypoplasia, and intellectual disability resulting from chromosomal microdeletion involving the COL4A5 gene and adjacent genes has been described [36].

DIAGNOSIS — The diagnosis of Alport syndrome is made by molecular genetic testing or skin or kidney biopsy (algorithm 1) [37].

If cost or accessibility is not an issue, we prefer using molecular genetic next-generation sequencing analysis to confirm the diagnosis of Alport syndrome (algorithm 1):

●Individuals, especially male patients, with a positive family history for persistent hematuria and/or kidney failure

●Patients with chronic kidney disease and sensorineural deafness and/or characteristic ocular findings regardless of family history

Molecular genetic testing — Molecular genetic testing is the diagnostic procedure of choice because it is noninvasive and has a high degree of sensitivity and specificity [38,39]. Since the rate of progression of kidney disease may be dependent on the underlying specific variant, molecular analysis may provide more reliable prognostic information than either kidney or skin biopsy.

The choice of molecular testing is based on whether there is a family history of Alport syndrome (algorithm 1):

●Family history of Alport syndrome – For patients with a family history of Alport syndrome with an identified pathogenic variant, targeted testing for the presumed gene variant is preferred. If targeted mutational analysis reveals that the patient has the same genetic variant as that identified in the patient's family member(s) with Alport syndrome, a diagnosis of Alport syndrome is confirmed. For patients in whom the targeted mutational analysis does not detect the same genetic mutation as that identified in the patient's family member(s) with Alport syndrome, a kidney biopsy is performed for diagnosis.

Direct mutational (targeted) analysis of coding sequence (ie, messenger ribonucleic acid [mRNA]), rather than genomic deoxyribonucleic acid (DNA), may provide a less laborious and more sensitive method for the detection of splice-site variants [40-43]. Since COL4A5 mRNA is expressed in the skin and hair roots, analysis of cells from these sites may allow a relatively noninvasive diagnostic test but may not be commercially available [40,44,45].

●Clinical features or nonspecific family history – For patients without a known family history of Alport syndrome but with clinical features suggesting this disorder (ie, kidney manifestations and either nonrenal findings [ocular and sensorineural deafness] or a family history of hematuria or kidney failure), next-generation DNA sequencing is performed. For patients in whom no pathogenic variant is detected, a kidney biopsy is performed for diagnosis.

Next-generation sequencing allows simultaneous analysis of the COL4A3, COL4A4, and COL4A5 genes and offers advantages in screening time and cost [46-48]. The large size and high GC content of the COL4A5 gene render direct mutational analysis of genomic DNA technically difficult. In addition, the analysis of genomic DNA may not detect large gene rearrangements or splice-site mutations [40,49].

●Other candidates for genetic testing – Other appropriate settings in which genetic testing may be beneficial include the following [50]:

•Prenatal diagnosis (due to family history of Alport syndrome)

•Confirmation or exclusion of the disorder in patients who cannot be unequivocally diagnosed by biopsy

•Absolute exclusion of the heterozygous state in an asymptomatic female

•When X-linked and autosomal disease cannot be differentiated by pedigree and immunohistochemical analysis

In addition, genetic testing may also be appropriate for selected patients from the following groups if there is a suspicion for Alport syndrome:

•Evaluation of persistent hematuria of undetermined etiology

•Genetic evaluation of patients with biopsy diagnosis of focal segmental glomerulosclerosis

•Genetic evaluation of patients with end-stage kidney disease of undetermined etiology

Current information on molecular testing for Alport syndrome can be obtained at GeneReviews and the Leiden Open Variation Database. As molecular testing decreases in cost and increases in availability, the indications for such testing are likely to expand [51].

Kidney and skin biopsy — In a kidney biopsy specimen, the characteristic finding of longitudinal splitting of the lamina densa of the glomerular basement membrane (GBM) detected by electron microscopy is diagnostic for Alport syndrome (picture 1A-B). However, in young patients, this characteristic appearance of a laminated GBM may not be present. In males with X-linked Alport syndrome, for example, the proportion of GBM showing splitting increases from approximately 30 percent by age 10 to more than 90 percent by age 30 [52]. Attenuation of the GBM is common in young males with X-linked Alport syndrome, young and mature females with X-linked Alport syndrome, young males and females with autosomal recessive Alport syndrome, and patients with autosomal dominant Alport syndrome. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Histologic changes'.)

If immunostaining for collagen IV is used and demonstrates absence or an abnormal distribution of the alpha-3, alpha-4 and/or alpha-5(IV) chains of the GBM, the diagnosis can be made in a patient with hematuria without the ultrastructural finding of a laminated GBM (figure 2). For example, immunostaining demonstrates absence of staining of the alpha-3, alpha-4, and alpha-5 (IV) chains in the GBM in approximately two-thirds of male patients and discontinuous distribution in many affected females with X-linked Alport syndrome. Bowman's capsules and distal tubule basement membranes may also show abnormal immunostaining for the alpha-3, alpha-4, and alpha-5 chains. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Immunostaining'.)

A less invasive potential method to diagnose a child with suspected X-linked Alport syndrome is a skin biopsy using commercially available monoclonal antibody against the alpha-5(IV) chain (picture 2) [2,50,53-56] (see "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Skin'). If the protein is clearly absent in a male (or is clearly mosaic in a female), a diagnosis of X-linked Alport syndrome can be made and should be followed by molecular testing if available. If the test demonstrates normal expression of the alpha-5(IV) chain, then the patient has one of the following:

●A variant in the COL4A5 gene that permits deposition of a functionally abnormal but antigenically normal alpha-5(IV) chain, which occurs in approximately 30 percent of male patients with X-linked disease

●Autosomal Alport syndrome with abnormalities in either the COL4A3 or COL4A4 gene

●Another disorder

In these uncertain cases, the diagnosis of Alport syndrome can subsequently be confirmed or excluded by a kidney biopsy with analysis of collagen IV expression in the kidney or by molecular genetic testing. A kidney biopsy should also be performed if results of a skin biopsy are equivocal and a diagnosis is required because of signs of progressive kidney disease, such as hypertension, proteinuria, or elevated plasma creatinine concentration. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Skin'.)

In up to 15 percent of cases, there is no identified family history of kidney disease [25] and the diagnosis is made by the presence of the characteristic lamination of the GBM, abnormal collagen IV immunostaining in skin or kidney, or identification of a pathogenic variant in COL4A3, COL4A4, or COL4A5 by molecular genetic analysis. These cases may represent de novo variants in the COL4A3, COL4A4, or COL4A5 genes or autosomal recessive disease [57].

DIFFERENTIAL DIAGNOSIS — Alport syndrome is typically differentiated from other major causes of persistent glomerular hematuria by a positive family history of hematuria associated with kidney failure and deafness. Other glomerular disorders that present in children with microscopic hematuria include IgA nephropathy, in which the family history is usually negative, and "thin basement membrane nephropathy" (TBMN), in which the family history may be positive for hematuria but kidney failure and deafness are typically absent or occur relatively late in life. However, some experts in the field including the author consider TBMN to be autosomal dominant Alport syndrome as these patients typically have a heterozygous variants in the COL4A3 or COL4A4 genes [1]. In addition, a normal serum complement component 3 (C3) level differentiates patients with Alport syndrome from those with C3 glomerulonephropathy. (See "Thin basement membrane nephropathy (benign familial hematuria)" and 'Diagnosis' above and "Isolated and persistent glomerular hematuria in adults".)

As noted above, the diagnosis of Alport syndrome is differentiated from other glomerular disease by confirmatory skin or kidney biopsy or molecular genetic testing. Alport syndrome is distinguished by the presence of the characteristic finding of lamination of the glomerular basement membrane (GBM) in samples from a kidney biopsy or abnormalities of collagen IV by immunostaining or by identification of pathogenic variant(s) in COL4A3, COL4A4, or COL4A5. As noted above, in this author's opinion, thin GBMs with or without focal segmental glomerulosclerosis in a patient with a COL4A3, COL4A4, or COL4A5 variant is properly diagnosed as Alport syndrome.

Megathrombocytopenia (thrombocytopenia with large or giant platelets) has been described in some families with an autosomal dominant-transmitted glomerulopathy and sensorineural deafness. This complex has been referred to as Epstein syndrome, or Fechtner syndrome when associated with leukocyte cytoplasmic inclusions. These disorders have been mapped to chromosome 22 and result from variants in the gene encoding nonmuscle myosin heavy chain 9 (MYH9). Variants in this gene can also cause Sebastian syndrome, another giant platelet disorder, and nonsyndromic hereditary deafness. These disorders are discussed separately. (See "Causes of thrombocytopenia in children", section on 'Large or giant platelets'.)

Thus, Epstein and Fechtner syndromes represent distinct disorders arising from variants in noncollagen genes, not variants of autosomal dominant Alport syndrome. In some patients, ultrastructural changes reminiscent of Alport syndrome may be present. However, immunostaining for type IV collagen in patients with Epstein or Fechtner syndrome is normal.

MANAGEMENT — In patients who develop kidney failure, kidney transplantation is the preferred modality for kidney replacement therapy.

There is no specific treatment for Alport syndrome. However, there is evidence that the use of angiotensin antagonists is beneficial in slowing progression of kidney disease.

Our approach — Our management approach follows the consensus clinical practice recommendations for the treatment of Alport syndrome as developed and updated by the Alport Syndrome Research Collaborative [58,59]. It consists of the following:

●Monitoring for kidney disease progression – Annual monitoring for microalbuminuria and proteinuria as soon as the diagnosis of Alport syndrome is made or beginning at one year of age for at-risk children.

●Renin-angiotensin system (RAS) blockade

•X-linked (males) and autosomal recessive disease – For male patients with X-linked Alport syndrome and for male and female patients with autosomal recessive Alport syndrome, angiotensin blockade therapy is provided at the time of diagnosis. If the diagnosis is made in infancy, treatment is withheld until the patient is between 12 and 24 months.

•Implementation – The choice and dosing of agents are based on data from the ESCAPE and EARLY-PROTECT trials [60,61]. We prefer using a long-acting angiotensin converting enzyme inhibitor such as ramipril or lisinopril, which require once-daily dosing.

-For ramipril, an initial dose is prescribed of 1.6 mg/m²/day, which is increased over three to four months to a maximum dose of 6 mg/m²/day or until the maximum tolerated dose is reached.

-For lisinopril, an initial dose is prescribed of 0.2 mg/kg/day, which is increased to a maximum dose of 10 mg/day or until the maximum tolerated dose is reached.

For pediatric patients, for both ramipril and lisinopril, the dose should be adjusted as the child grows to maintain a constant dose based on weight.

In the case of patients who are not yet exhibiting albuminuria or proteinuria at the time treatment is initiated, the escalation scheme is based on patient tolerance rather than urinary albumin or protein measurements.

In patients who have proteinuria at the time of diagnosis, the same escalation strategy is used. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Issues with measuring urine albumin' and 'Phenotype-genotype correlation' above.)

If urine protein-creatinine ratio remains greater than 1.0 mg/mg despite maximal ramipril or lisinopril dosing, dual angiotensin blockade with the addition of an angiotensin-receptor blocker can be considered. In a small group of pediatric patients, addition of losartan at an initial dose of 0.8 mg/kg/day reduced urine protein levels by approximately 60 percent [62]. The addition of aldosterone inhibition to angiotensin blockade also reduced proteinuria in children with Alport syndrome, according to the findings of two small case series [63,64].

•Autosomal dominant disease and females with X-linked disease – In females with X-linked Alport syndrome and males and females with autosomal dominant Alport syndrome, angiotensin blockade therapy is initiated when the patient exhibits persistent microalbuminuria (urine microalbumin/creatinine ratio >30 mg/g). We recommend using the same dosing protocols of ramipril and lisinopril as in males with X-linked Alport syndrome. Effective contraception is mandatory for menstruating female patients to prevent fetopathy secondary to angiotensin blockade during pregnancy.

•Monitoring of patients receiving angiotensin blockade – We recommend serum electrolytes, kidney function, and urine albumin and/or protein measurement every six months in patients receiving angiotensin blockade therapy, with closer monitoring in patients with more advanced chronic kidney disease. In our experience, hyperkalemia is unusual among Alport syndrome patients treated with angiotensin blockade who have normal kidney function. For patients who develop hyperkalemia, management options include dietary potassium restriction, use of a potassium-chelating agent such as patiromer, and reducing or discontinuing angiotensin blockade. (See "Management of hyperkalemia in children", section on 'Chronic hyperkalemia'.)

●Supportive care – Other supportive measures are initiated to prevent and treat complications of chronic kidney disease, which are discussed separately. (See "Chronic kidney disease in children: Overview of management".)

•Kidney transplantation is the preferred option over dialysis for patients who develop kidney failure. There is a small, but not insignificant, risk of developing anti-glomerular basement membrane (anti-GBM) antibody disease in the allograft. (See 'Anti-GBM antibody disease' below.)

•Supportive measures are used for hearing loss (eg, hearing aids) and ocular impairment as there are no interventions that correct hearing loss and ocular defects.

Renin-angiotensin blockade — Several studies have demonstrated that RAS blockade therapy reduces proteinuria and diminishes the rate of glomerulosclerosis and disease progression in patients with Alport syndrome [65-71]. Additional data suggest that early RAS blockade therapy is beneficial and safe in patients who have microalbuminuria but who have not yet developed overt proteinuria [60,71]. As a result, the clinical practice recommendations from the Alport Syndrome Research Collaborative were updated to initiate earlier intervention [59]. These guidelines recommend initiation of RAS blockade at the time of diagnosis in males with X-linked Alport syndrome and males and females with autosomal recessive Alport syndrome, whether or not there is microalbuminuria or proteinuria, and in females with X-linked Alport syndrome and males and females with autosomal dominant Alport syndrome if there is persistent microalbuminuria. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults" and "Nonemergent treatment of hypertension in children and adolescents", section on 'ACE inhibitors' and "Nonemergent treatment of hypertension in children and adolescents", section on 'Chronic kidney disease'.)

●In a large study of patients with Alport syndrome followed by the European Alport Registry for a mean duration of over 20 years, a retrospective analysis found that initiation of ACE inhibitors delayed dialysis in patients with proteinuria and normal kidney function compared with those who never received such therapy or who received treatment only when they developed impaired kidney function (dialysis initiated at a mean age of 40, 22, and 25 years, respectively) [67]. In a subsequent prospective report, RAS blockade therapy was also effective in preventing progression in kidney function deterioration for patients with autosomal or X-linked Alport syndrome with heterozygous mutations in type IV collagen genes [69].

●In a large retrospective study of Japanese patients with X-linked disease, treatment with RAS blockade therapy was associated with a delay in the onset of kidney failure (previously referred to end-stage kidney disease) [70]. Exposure to RAS blockade therapy versus no exposure delayed kidney failure with both truncating (median age 28 versus 16 years) and nontruncating mutations (median age 50 versus 33 years).

Other drugs (not recommended)

Cyclosporine — Data are inconclusive regarding the benefit of cyclosporine to improve kidney survival, and cyclosporine is associated with nephrotoxicity. As a result, until further data demonstrate benefit from cyclosporine therapy, we do not suggest that this agent be used in patients with Alport syndrome to slow the progression of kidney disease.

In humans, uncontrolled studies of cyclosporine therapy have produced divergent results. In a Spanish study of eight patients who ranged in age from 15 to 27 years of age at follow-up, serum creatinine values remained stable compared with pretreatment measurements after a mean duration of cyclosporine therapy of 8.4 years [72]. In addition, patients had either a lower or equivalent degree of proteinuria compared with baseline values. In contrast, a study of nine French patients reported that cyclosporine therapy suppressed proteinuria but reduced glomerular filtration rate and possibly accelerated renal fibrosis [73]. In an uncontrolled study of Italian children with Alport syndrome, cyclosporine therapy transiently reduced proteinuria but did not prevent subsequent decline in kidney function [74].

In a canine model of X-linked Alport syndrome, cyclosporine treatment failed to diminish proteinuria but resulted in longer kidney survival [75].

SGL2 inhibition — The possible role of sodium glucose-like cotransporter-2 (SGL2) inhibition in Alport syndrome is uncertain due to a paucity of relevant data [76]. Although a two-year, double-blind, placebo-controlled, randomized trial of bardoxolone therapy found higher estimated glomerular filtration rates in treated patients, bardoxolone has not been approved by the US Food and Drug Administration for treatment of Alport syndrome, due to concerns regarding safety and the significance of the effect on estimated glomerular filtration rate [77].

Kidney transplantation — Patients with Alport syndrome typically have excellent kidney transplant outcomes. Recurrent disease does not occur in the transplanted graft, because the donor kidney has a normal GBM. However, anti-GBM antibody disease (anti-GBM antibody disease) occurs in approximately 3 percent of affected males who receive transplants.

Anti-GBM antibody disease — Because the incidence of clinical anti-GBM antibody disease is low, kidney transplantation is not contraindicated in patients with Alport syndrome [42]. De novo anti-GBM antibody disease (also referred to as Alport post-transplant nephritis) develops in approximately 3 percent of transplanted males [17,25,53,78-84]. In males with X-linked disease, antibodies are directed primarily against the alpha-5(IV) chain, but antibodies against the alpha-3(IV) chain are also found in some patients [27,78,81,84-86]. In patients with autosomal recessive Alport syndrome who develop Alport post-transplant nephritis, the predominant target of anti-GBM antibodies is the alpha-3(IV) chain [86,87]. Patients with autosomal dominant Alport syndrome do not appear to be at increased risk for de novo anti-GBM disease after kidney transplantation.

The vast majority of cases of Alport post-transplant nephritis occur in males. This is consistent with the hypothesis that even a female heterozygote who developed kidney failure would have some cells synthesizing and secreting a normal alpha-5(IV) chain; thus, a transplanted kidney would not be expressing a new antigenic epitope to these patients. However, Alport post-transplant nephritis has been described in females with autosomal recessive disease [87,88]. In these patients, the anti-GBM antibodies are directed primarily against the alpha-3(IV) chain.

Although anti-GBM antibody disease usually occurs in the first year after transplantation, an interval of several years between transplantation and presentation with Alport post-transplant nephritis can occur [53]. Affected patients typically have circulating anti-GBM antibodies, and up to three-quarters of patients may develop crescentic glomerulonephritis and loss of the graft [53,79,80].

The key to early diagnosis of Alport post-transplant nephritis is a low threshold for obtaining an allograft biopsy with immunofluorescence, which demonstrates the characteristic finding of linear deposition of IgG along the glomerular capillaries and, occasionally, the distal tubules. The clinician should not rely solely on commercial anti-GBM assays, because they are optimized for detection of antibodies directed against the Goodpasture antigen rather than antibodies against the alpha-5(IV) chain. (See "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis", section on 'Evaluation and diagnosis'.)

Plasmapheresis and immunosuppression with methylprednisolone and cyclophosphamide, which are initially used in treating primary anti-GBM disease, have been of limited benefit in post-transplant disease but may be helpful [53]. In our center, we treat patients with primary anti-GBM disease with a combination of plasmapheresis and cyclophosphamide. Retransplantation in these patients is associated with a high risk of recurrence (seven of eight in one report) [53]. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)

The optimal management in patients who lost their first graft to Alport post-transplant nephritis and whether a second transplant should be performed are uncertain. The recurrence rate is high in subsequent transplants [43,85], but isolated cases of successful retransplantation have been reported [79].

It is unclear why only some patients develop anti-GBM antibody disease after transplantation. In patients with X-linked disease, the specific type of mutation may be an important factor in developing anti-GBM antibody disease. The risk appears to be greatest in patients with COL4A5 variants that prevent synthesis of the alpha-5(IV) chain [80,82,85]. This was illustrated in one review of Alport patients with post-transplant anti-GBM disease that reported 54 percent (7 of 13) of patients with anti-GBM disease had large deletions in the COL4A5 gene compared with a deletion frequency of 16 percent in all patients with Alport syndrome [82].

However, a COL4A5 gene deletion alone does not appear to be sufficient to cause anti-GBM disease following kidney transplantation. In one study, only one of seven patients with a COL4A5 deletion and complete absence of the alpha-5(IV) chain developed anti-GBM disease in the kidney transplant [27], suggesting that factors other than exposure to a previously unseen antigen must be involved. The complex interplay between the host's underlying gene defect, immune response factors such as antigen presentation, and immunosuppression are all factors that must be considered in the development of post-transplant anti-GBM disease [89].

Differences in the ability to activate the cellular arm of the immune system may be another reason why only some patients develop Alport post-transplant nephritis. One study evaluated the variation in anti-GBM antibody formation in patients with Alport syndrome in whom post-transplant disease had or had not developed (12 and 10 patients, respectively) [41]. All patients in both groups displayed some combination of antibodies directed against the alpha 3, 4, or 5 chains of collagen IV, and the pattern of antibody expression did not differ between the two groups. It has also been noted that some Alport patients develop linear immunoglobulin G (IgG) staining of the transplant GBM, without concomitant evidence of complement component 3 (C3) deposition, glomerulonephritis, or allograft dysfunction [79]. These data suggest that nonhumoral immune factors contribute to the variation in the frequency of anti-GBM disease post-transplant.

Living-related donors — Since Alport syndrome is a familial disorder, potential living-related kidney donors for Alport patients must be carefully evaluated [90-92].

●Male relatives of a patient with X-linked Alport syndrome who do not have hematuria are suitable candidates.

●Females who are heterozygous for X-linked Alport syndrome should not be a donor unless:

•They are asymptomatic without evidence of hematuria (approximately 5 percent of individuals) and understand and accept that there is a 50 percent risk of transmitting the COL4A5 variant with each pregnancy. This would mean that if they donate a kidney to a male relative prior to childbearing, the female could not subsequently be a donor to an affected son.

•They are over 45 years of age with normal urine protein excretion, normal hearing by audiogram, and normal kidney function. However, they would be donors of last resort.

●Males and females who are heterozygous for a COL4A3 or COL4A4 variants may be suitable donors to a recipient with autosomal recessive Alport syndrome if they have normal urine protein excretion and kidney function. However, if the heterozygous state is associated with chronic kidney disease or kidney failure, donation would not be advisable.

SUMMARY AND RECOMMENDATIONS

●Genetics – Alport syndrome is a genetically heterogeneous disease that results from mutations in genes encoding the alpha-3, alpha-4, and alpha-5(IV) chains of collagen IV and that can be transmitted in a X-linked, autosomal recessive, or autosomal dominant fashion. (See 'Genetics' above.)

●Clinical features

•The abnormal chains of collagen IV cause basement membrane impairment in the glomerulus, eye, and inner ear, resulting in the clinical findings of Alport syndrome.

•The classical presentation of Alport syndrome is based on clinical manifestations of affected males with X-linked disease. These features include glomerular disease that progresses to kidney failure, ocular abnormalities (eg, anterior lenticonus), sensorineural hearing loss, and positive family history of kidney failure and hearing loss.

•Patients with autosomal recessive disease have a similar clinical presentation and course as those with X-linked disease, whereas patients with autosomal dominant disease generally have a slower deterioration of kidney function and are less likely to exhibit sensorineural deafness and ocular abnormalities. (See 'Clinical manifestations and course' above.)

•The initial kidney manifestation of Alport syndrome is usually asymptomatic microscopic hematuria. Gross hematuria may also be a presenting finding, which may occur after an upper respiratory infection. The serum creatinine and blood pressure are normal in early childhood, but progressive insufficiency, hypertension, and increasing proteinuria develop with time. Kidney failure usually occurs in affected males with X-linked disease between the ages of 16 and 35, but the course is more indolent in some families. (See 'Kidney manifestations' above.)

•Females with X-linked Alport syndrome are heterozygous for the COL4A5 gene variant and have a range of clinical findings due to lyonization, in which only one X chromosome is active per cell. (See 'Phenotype-genotype correlation' above.)

●Diagnosis – The diagnosis of Alport syndrome is made by molecular genetic analysis (preferred if cost is not an issue) or skin or kidney biopsy with characteristic findings of Alport syndrome (algorithm 1). (See 'Diagnosis' above.)

●Management – (See 'Our approach' above.)

•There is no specific treatment to correct the underlying defect for Alport syndrome.

•In patients with Alport disease and overt proteinuria, angiotensin blockade therapy reduces the rate of protein excretion and appears to slow the progression of the disease. As a result, annual monitoring for microalbuminuria and proteinuria is performed as soon as Alport syndrome is diagnosed.

•We suggest early renin-angiotensin system (RAS) blockade for patients with Alport disease either with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) (Grade 2B). (See 'Renin-angiotensin blockade' above.)

•We do not suggest cyclosporine therapy in patients with Alport syndrome (Grade 2C). Cyclosporine has not been shown to reduce the rate of kidney disease progression and has significant side effects including cyclosporine toxicity. (See 'Cyclosporine' above.)

•For patients who develop kidney failure, the preferred modality of kidney replacement therapy is kidney transplantation. Recurrent disease does not occur in the transplant (since the donor glomerular basement membrane [GBM] is normal); however, approximately 3 percent of transplanted males develop de novo anti-GBM antibody disease. (See 'Kidney transplantation' above and 'Anti-GBM antibody disease' above.)

•Supportive measures are used for hearing loss (eg, hearing aids) and ocular impairment in affected patients.