Review

Alport Syndrome: Achieving Early Diagnosis and

Treatment
Clifford E. Kashtan

Alport syndrome is a genetically and phenotypically heterogeneous disorder of glomerular, cochlear, Complete author and article
and ocular basement membranes resulting from mutations in the collagen IV genes COL4A3, information provided before
references.
COL4A4, and COL4A5. Alport syndrome can be transmitted as an X-linked, autosomal recessive, or
autosomal dominant disorder. Individuals with Alport syndrome have a significant lifetime risk for kidney Am J Kidney Dis.
failure, as well as sensorineural deafness and ocular abnormalities. The availability of effective inter- 77(2):272-279. Published
online July 22, 2020.
vention for Alport syndrome–related kidney disease makes early diagnosis crucial, but this can be
impeded by the genotypic and phenotypic complexity of the disorder. This review presents an doi: 10.1053/
approach to enhancing early diagnosis and achieving optimal outcomes. j.ajkd.2020.03.026
© 2020 by the National
Kidney Foundation, Inc.

Introduction A working group of clinicians including nephrologists

The modern era of Alport syndrome can be said to have
begun in the 1970s with reports of unique ultrastructural
abnormalities in glomerular basement membranes of pa-
tients with the disease.1-3 These seminal observations initi-
ated a cascade of investigation that led to the identification
of collagen IV as the protein locus of Alport syndrome4,5;
the cloning and sequencing of the COL4A3, COL4A4, and
COL4A5 genes6-8; the discovery of variants in these genes in
Alport syndrome families6,7,9; and the generation of trans-
genic Alport mice.10-12 The availability of these mice led to
arguably the most important recent development in Alport
syndrome research: the demonstration that the natural his-
tory of Alport syndrome–related kidney disease can be
ameliorated using relatively safe and inexpensive in-
terventions.13 Although the interventions currently available
are not curative, they can dramatically delay progression to
kidney failure, especially if initiated before there is any
reduction in glomerular filtration rate (GFR).14 Given that
the progression of the Alport nephropathy can be modified
by early intervention, there is an imperative for the early
diagnosis of Alport syndrome. This review presents an
approach to evaluating patients that aims to promote the
early diagnosis and treatment of Alport syndrome.
A fundamental feature of diseases of the network of
collagen type IV α3, α4, and α5 chains (the collagen IV
α345 network) is phenotypic heterogeneity, resulting in a
broad range of kidney outcomes and extrarenal manifes-
tations. This heterogeneity challenges us to create a
nomenclature that will provide effective guidance to a
diverse group of stakeholders that includes a variety of
clinicians, such as nephrologists, geneticists and genetic
counselors, pathologists, otolaryngologists and audiolo-
gists, and ophthalmologists; investigators in basic and
translational research in academia and the pharmaceutical
industry; and patients and their families and advocacy
groups. In developing this nomenclature, we must be
careful to avoid erecting artificial barriers to early diagnosis
and optimal care.
and geneticists set out to develop an inclusive classification
of genetic disorders of the collagen IV α345 network to
expedite the diagnosis and initiation of therapy aimed at
delaying progression to kidney failure.15 This group pro-
posed that the diagnosis of Alport syndrome should be
applied to individuals with any genetic variant that in-
terferes with the normal synthesis, deposition, and func-
tion of the collagen IV α345 network of basement
membranes. According to this scheme, the Alport pheno-
type ranges from a nonprogressive kidney-limited disorder
to progressive multisystem disease, and the genetic spec-
trum includes X-linked, autosomal recessive, autosomal
dominant, and digenic inheritance (Table 1).
This approach relies primarily on the results of gene
sequencing, with less emphasis on specific extrarenal signs
and symptoms and kidney pathology findings than previ-
ous classification schemes. In addition, this approach
changes some of the ways that we think about people with
variants that affect the collagen IV α345 network.
According to this classification, women with heterozy-
gous variants in COL4A5 are not “carriers” of X-linked
Alport syndrome; rather they actually have X-linked Alport
syndrome and are at risk for progressive kidney disease.
Similarly, individuals with heterozygous variants in
COL4A3 or COL4A4 are not only carriers of autosomal
recessive Alport syndrome but they are also at risk for
progressive kidney disease, that is, autosomal dominant
Alport syndrome, especially if they exhibit hematuria.
Patients with glomerular basement membrane thinning
and a variant in COL4A3, COL4A4, or COL4A5 are classified
as having Alport syndrome, with the result that “thin
basement membrane nephropathy” (a description based
on pathology rather than a distinct disease entity) is
eliminated as a diagnosis. Finally, patients with focal
segmental glomerulosclerosis on biopsy and a variant in
COL4A3, COL4A4, or COL4A5 are considered to have Alport
syndrome, rather than a genetic form of focal segmental
glomerulosclerosis.

272 AJKD Vol 77 | Iss 2 | February 2021

Kashtan
Table 1. Alport Syndrome Classification
Affected
Inheritance Gene(s) Genetic State
X-Linked COL4A5 Hemizygous (males)
Heterozygous (females)
Autosomal COL4A3 or Recessive (homozygous or
COL4A4 compound heterozygous)
Dominant (heterozygous)
Digenic COL4A3, COL4A3 & COL4A4 variants in
COL4A4, and trans (recessive)
COL4A5 COL4A3 & COL4A4 variants in
cis (dominant)
Variants in COL4A5 and in
COL4A3 or COL4A4 (non-
Mendelian)
Suspected — Clinical, pedigree, tissue data
are highly suggestive of Alport
syndrome but genetic data are
not confirmatory
There are multiple advantages to this approach. Making
the diagnosis of Alport syndrome establishes that an in-
dividual has a familial disease that carries the risk for
progression to kidney failure, which should result in close
monitoring of the patient and evaluation of at-risk rela-
tives. Early diagnosis of Alport syndrome facilitates
monitoring for the onset of albuminuria and proteinuria,
the current indications for initiating treatment with
angiotensin II antagonists.16 A diagnosis of Alport syn-
drome allows connection with strong patient advocacy and
support groups such as the Alport Syndrome Foundation
(alportsyndrome.org).
Expedited diagnosis is important in adults and children.
The higher the GFR when treatment is initiated, the greater
the delay in progression to kidney failure.14 In addition,
diagnosis in adults, even those who have already advanced
to kidney failure,17 creates the opportunity to establish the
diagnosis in related adults and children who can benefit
from intervention.
There are also obstacles to this approach. In the United
States, insurance coverage for gene sequencing is variable and
the cost may exceed a family’s financial means. Some variants
in COL4A3, COL4A4, and COL4A5 will go undetected by cur-
rent sequencing methods. People may fear a return to the
pre–Affordable Care Act era, when those with pre-existing
conditions could be denied health insurance or charged
enormous premiums. Nevertheless, nephrologists should
take every opportunity to diagnose, monitor, and treat Alport
syndrome before kidney function begins to decline.
What Is Alport Syndrome?
The consensus definition of Alport syndrome has evolved
during the past several decades. In the 1980s, deafness was
considered essential for the diagnosis; one study stated
“Since Alport emphasized that deafness was an integral
part of the syndrome, we suggest that the eponym Alport’s
syndrome should be reserved for patients affected with the
same disease as Alport’s family.”18(p 1007) Male patients
AJKD Vol 77 | Iss 2 | February 2021
with Alport syndrome were characterized as developing
kidney failure in their teens or early twenties.18 This nar-
row definition of the Alport phenotype facilitated genetic
linkage studies that mapped the first known Alport locus to
the long arm of the X chromosome19,20 and the
sequencing studies that identified COL4A5 as the locus for
X-linked Alport syndrome.9 However, subsequent studies
established a much broader phenotypic spectrum for males
with COL4A5 variants, with kidney failure and deafness
frequently delayed until age 40 to 60 years.21-23 This is a
familiar paradigm for genetic diseases when the locus is
unknown: initial studies use a constricted phenotypic
definition to minimize potential genetic heterogeneity and
then when a gene is implicated, heterogeneity of pheno-
types associated with variants in that gene is revealed.
The identification of COL4A5 as the locus for X-linked
Alport syndrome was rapidly followed by the cloning and
sequencing of COL4A3 and COL4A4 and the discovery of
homozygous and compound heterozygous variants in
these genes in patients with autosomal recessive Alport
syndrome.6,7 Eventually heterozygous variants in these
genes were found in families with autosomal dominant
transmission of a nephropathy with characteristic ultra-
structural features of Alport syndrome,24-27 firmly estab-
lishing the existence of an autosomal dominant form of
Alport syndrome, a hypothesis that had been advanced by
some groups28,29 but questioned by others.18 Although the
precise proportion of Alport cases attributable to the
autosomal dominant form has not been defined, it appears
to account for a substantially greater fraction of affected
individuals than previously understood.24,25
The complexity of Alport genotype-phenotype re-
lationships does not end there. Females heterozygous for
COL4A5 variants were long considered to be carriers of X-
linked Alport syndrome but they are clearly at risk for
kidney failure and deafness.30-32 Some people with het-
erozygous variants in COL4A3 or COL4A4 are asymptomatic
and many have only isolated microhematuria, at least at the
time of study, with or without demonstration of thin
glomerular basement membranes.6,7 Ocular manifestations
of Alport syndrome such as anterior lenticonus and reti-
nopathy33,34 are dependent on collagen type IV genotype,
age, and sex. These signs are extremely useful diagnosti-
cally but are frequently absent or go undetected.
And there is more. Two forms of “digenic” inheritance
in Alport families have been reported. Families may
transmit variants in 2 of the Alport loci (COL4A3, COL4A4,
or COL4A5), potentially resulting in non-Mendelian in-
heritance patterns and phenotypic heterogeneity within
the family.35 Or families may transmit a COL4A variant
along with a variant in a noncollagen gene, potentially
resulting in a more severe phenotype.36-40
How do we organize this genetic and phenotypic het-
erogeneity into a coherent classification scheme that is
accessible and useful to patients and families, the clinicians
who care for them, and investigators developing novel
treatments for Alport syndrome while also facilitating
273

expedited diagnosis and treatment? There are significant
advantages associated with an inclusive classification that
organizes the genetic disorders of the collagen IV α345
network under a single tent, rather than attempting to
arbitrarily divide these disorders into discrete entities by
phenotype (Table 1). Furthermore, classification of these
disorders as forms of Alport syndrome provides a “home”
for patients and families and clear points of contact for
clinicians and investigators.
Achieving Early Diagnosis of Alport Syndrome
Urinalysis is an extremely effective method of screening
for Alport syndrome. All males with X-linked Alport syn-
drome, as well as all males and females with autosomal
recessive Alport syndrome, have persistent micro-
hematuria. In females who are heterozygous for X-linked
Alport syndrome, the likelihood of microhematuria is
95%, although it may be intermittent.30 Some individuals
with heterozygous variants in COL4A3 or COL4A4 are
asymptomatic6,7; the risk for developing chronic kidney
disease (CKD) in these individuals is uncertain but is
probably lower than for those with microhematuria.
Consequently, screening urinalyses of at-risk family
members should be carried out whenever the diagnosis of
Alport syndrome is made.
Alport syndrome should be in the differential diagnosis
of patients with persistent glomerular hematuria, whether
identified by routine urinalysis, presentation with gross
hematuria, or discovery of microhematuria during evalu-
ation for possible urinary tract infection or other urinary
tract disorders. The absence of a family history of hema-
turia or CKD does not rule out Alport syndrome.
Approximately 12% of children with X-linked Alport
syndrome have de novo variants,23 and a negative family
history of kidney disease is common in patients with
autosomal recessive Alport syndrome. Furthermore, fam-
ilies may be unaware that relatives have hematuria or CKD,
or CKD may have been attributed to aging or other dis-
orders such as diabetes. Extrarenal manifestations such as
sensorineural deafness and ocular anomalies are influenced
by age, genotype, and, in X-linked Alport syndrome, by
sex, and therefore their absence does not rule out Alport
syndrome. Hearing loss is unusual in autosomal dominant
Alport syndrome, affecting 4% to 13% of individuals,26,41
as are ocular lesions.
Although routine examination of urine in the school-
age population would enhance the diagnosis of Alport
syndrome, children in the United States do not undergo
routine screening urinalysis. The recommendation of the
American Academy of Pediatrics is that screening urinalysis
should be limited to children “who are at high risk for
chronic kidney disease, such as those with a history of
chronic kidney disease, acute kidney injury, congenital
anomalies of the urinary tract, acute nephritis, hyperten-
sion, active systemic disease, prematurity, intrauterine
growth retardation or a family history of genetic renal
274
Kashtan
disease.”42 This recommendation is based on studies
showing that routine screening urinalysis is associated
with a high false-positive/transient abnormality rate and a
low yield of detection of treatable problems in the healthy
pediatric population, creating a relatively poor cost-benefit
relationship.43 Although the true prevalence of Alport
syndrome in the United States is uncertain, it is likely that
screening urinalyses in the school-age population would
identify a significant number of affected children. Would
the early identification and treatment of affected children
result in a benefit greater than the economic and emotional
costs associated with false-positive urinalyses? This should
remain an open question to be revisited as we learn more
about the epidemiology of Alport syndrome and the effi-
cacy of early intervention.
What are the proper roles of tissue biopsy and genetic
testing in the evaluation of individuals with persistent
glomerular hematuria? As argued in this review, there is
potentially a very large benefit associated with early
diagnosis of Alport syndrome. The value of this benefit
must be weighed against the risks of kidney biopsy and the
costs, financial and otherwise, of genetic testing (Boxes 1
and 2). In some cases, the diagnostic benefit will not
accrue principally to the individual undergoing biopsy or
genetic testing, for example, in the case of a patient with
CKD or kidney failure, but primarily to the patient’s
children or relatives.
In the pediatric population, the major causes of
persistent isolated glomerular hematuria with normal
serum complement levels include immunoglobulin A ne-
phropathy (IgAN) and the conditions associated with
variants in the COL4A3, COL4A4, and COL4A5 genes, which,
as described, can be grouped together as Alport syndrome.
These diagnoses have different implications. Children with
Box 1. Indications for Genetic Testing for Alport Syndrome
(COL4A3, COL4A4, and COL4A5 Genes)
Persistent glomerular hematuria, plus ≥1 of the following:
• Clinical findings
> Sensorineural deafness
> Anterior lenticonus and/or characteristic retinopathy
• Family history findings
> Hematuria
> CKD/kidney failure
> Deafness associated with CKD
• Pathologic findings on kidney biopsy
> Negative or nonspecific routine immunofluorescence
> Thin glomerular basement membranes
> Characteristic glomerular basement membrane thickening,
lamellation, and scalloping
• Other
> Steroid-resistant FSGS (as part of NGS panel for FSGS,
or WES)
Abbreviations: CKD, chronic kidney disease; FSGS, focal segmental glomer-
ulosclerosis; NGS, next-generation sequencing; WES, whole-exome
sequencing.
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Kashtan
Box 2. Genetic Testing for Alport Syndrome: Advantages and
Limitations
Advantages
• Confirmation of diagnosis
• Genotype has implications for:
> Prognosis and monitoring
> Identification of at-risk relatives
> Predicting risk for recurrence in future pregnancies
> Personalized treatment (future)
Limitations
• w10% of patients with clinically and pathologically confirmed
Alport syndrome have mutations that are not identified by
NGS or WES
• Significance of some variants will be uncertain
• Insurance coverage is variable
• Access to genetic counseling is variable
Abbreviations: NGS, next-generation sequencing;
sequencing.
IgAN who present with isolated hematuria frequently have
static disease for years, whereas children with Alport
syndrome have a significant risk for progression to overt
proteinuria, CKD, and kidney failure, a risk that can be
modified with early intervention. Unlike IgAN, Alport
syndrome is frequently associated with important extra-
renal problems and commonly affects related individuals.
Children with Alport syndrome frequently develop
sensorineural deafness that can be identified and managed
before it becomes clinically symptomatic. Finally, a diag-
nosis of Alport syndrome establishes risks for the child’s
parents, siblings, and other relatives. For these reasons, it is
crucial to establish the diagnosis of Alport syndrome
whenever possible and as early as possible. Figure 1 de-
scribes one possible approach.
Clinical/pedigree data
suggest diagnosis of
Alport syndrome
Gene c tes ng
Pathogenic variant
iden fied
Manage as Alport syndrome:
regular follow-up, start ACEi in
all proteinuric pa ents**
Figure 1. An approach to the diagnosis of individuals with persistent glomerular hematuria using kidney biopsy and/or genetic
testing. *Kidney biopsy should always include routine transmission electron microscopy (TEM). When TEM shows glomerular base-
ment membrane changes suggestive of Alport syndrome, immunofluorescence studies of collagen IV α chain expression can provide
useful diagnostic and prognostic information. Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; VUS, variant of uncertain
significance.
AJKD Vol 77 | Iss 2 | February 2021
The approach suggested in Fig 1 can also apply to adults
with persistent glomerular hematuria. A diagnosis of
Alport syndrome in an adult is associated with a modifiable
risk for CKD and kidney failure, extrarenal complications,
and potentially affected relatives. Although adult patients
with isolated hematuria of glomerular origin may not
require a kidney biopsy,44 they deserve a specific diag-
nosis, which may be provided by genetic testing. As in
children, the diagnosis of Alport syndrome in
adults should ideally be made before the onset of overt
proteinuria and certainly before GFR begins to
decline.14,45
Tissue studies remain important in the diagnostic
evaluation of patients with persistent glomerular hematuria
despite the increasing availability of genetic testing.
Assessment of kidney biopsy specimens should include
electron microscopy, as well as light microscopy and
WES, whole-exome
routine immunofluorescence. When routine immunoflu-
orescence shows negative or nonspecific immunoreactant
deposition, collagen IV immunostaining can provide both
diagnostic and prognostic information46-48 that is useful
even if electron microscopy cannot be performed. Skin
biopsy with collagen IV immunostaining is a possible
alternative to kidney biopsy for the diagnosis of X-linked
Alport syndrome but cannot exclude IgAN or identify
autosomal forms of Alport syndrome.49
It is important to avoid minimizing the limitations
associated with genetic testing (Box 2). Laboratories
generally use standard terminology to describe sequence
variants—pathogenic, likely pathogenic, uncertain signif-
icance, likely benign, and benign—based on specific types
of evidence, including population data, computational
data, functional data, and segregation data,50 but it is
possible that a substantial proportion of nephrologists are
uncomfortable interpreting these reports and discussing
Persistent glomerular hematuria
with normal serum complement
Clinical/pedigree data
nega ve
Kidney biopsy*
Findings suggest Findings indicate
No variant, benign variant, Alport syndrome non-Alport kidney
or VUS disease
Manage as Alport syndrome: Appropriate
regular follow-up, start ACEi in management
all proteinuric pa ents**
proceed to gene c tes ng
(if not already done)
275

the results with their patients. In the United States, pa-
tients’ access to genetic counseling services is often
limited, and they may have variable and often inadequate
insurance coverage. Despite these issues, the opportunities
that genetic testing offers for meaningful interventions
should be pursued when possible.
Treatment of Alport Kidney Disease
Alport nephropathy progresses through a consistent set of
milestones, beginning with isolated hematuria, followed
by moderate albuminuria, severe proteinuria, and decline
in GFR, in that order. The interval between milestones
varies from patient to patient and is influenced primarily
by sex and COL4A genotype. The spectrum of progression
rate is very broad, ranging from very rapid, requiring
kidney replacement therapy in adolescence or early
adulthood, to very slow with death at an advanced age
with normal kidney function.
Currently, the goal of therapy of Alport kidney disease is
to safely lengthen the intervals between the milestones of
progression to the greatest extent possible. Data from
experimental and human research indicate that this goal
can be accomplished effectively with angiotensin-
converting enzyme (ACE) inhibitor treatment, achieving
optimal results when initiated before GFR begins to
decline.13,14,51 According to a recent consensus statement,
treatment should be initiated in all patients with overt
proteinuria, aiming for the maximal recommended dose
(based on a maximal ramipril dosage of 6 mg/m2 per day
in children) that the patient will tolerate.16 Moderate
albuminuria is an indication for initiation of treatment in
male patients with COL4A5 variants predictive of rapid
progression to kidney failure and in male and female pa-
tients with autosomal recessive Alport syndrome.16 In in-
dividuals who have moderate albuminuria and in whom
progression is likely to be relatively gradual (males with
COL4A5 missense variants, females with heterozygous
COL4A5 variants, and males and females with heterozygous
COL4A3 and COL4A4 variants), the risks of ACE-inhibitor
treatment, including fetal injury, must be balanced
against the potential benefit.
It is unclear how COL4A genotype may influence the
response to ACE-inhibitor therapy. It is entirely conceivable
that those with relatively favorable genotypes (eg, men with
COL4A5 missense variants, women with heterozygous
COL4A5 variants, and those with heterozygous COL4A3 and
COL4A4 variants) will experience the best treatment
outcome: avoiding kidney failure. These are precisely the
patients who are most likely to be undiagnosed or labeled as
“benign familial hematuria” or “thin basement membrane
nephropathy” because of their relative paucity of symp-
toms, thereby losing the opportunity for early intervention.
Could better outcomes be achieved if ACE-inhibitor
therapy is initiated before the onset of overt protein-
uria? This question is being examined by the EARLY-
PROTECT trial, in which children with Alport
276
Kashtan
syndrome who have isolated hematuria or hematuria
and moderate albuminuria are randomly assigned to
placebo or ramipril treatment.52 Treatment recommen-
dations are likely to change if this trial shows that
ramipril therapy delays progression from isolated he-
maturia to hematuria and moderate albuminuria and/or
moderate albuminuria to overt proteinuria.
In addition to the EARLY-PROTECT trial, two ran-
domized trials of novel therapies for Alport kidney disease
are in progress (see disclosure information at end of
article). The CARDINAL trial (ClinicalTrials.gov Identifier
NCT03019185) is a phase 2/3 trial examining the safety,
tolerability, and efficacy of bardoxylone methyl (an acti-
vator of the transcription factor Nrf2), using the increase
in estimated GFR from baseline to 48 weeks of treatment as
the primary outcome. The HERA trial (ClinicalTrials.gov
Identifier NCT02855268) is a phase 2 trial of the
anti–microRNA 21 agent SAR339375, with adverse events
and annualized change in estimated GFR as primary out-
comes. These trials are discussed in greater detail in two
excellent recent reviews.53,54
The need for investigation of curative treatments must
be balanced against the generally very successful outcomes
of kidney transplantation for kidney failure due to Alport
syndrome,55-57 which should inform consideration of the
risks for adverse events. Patient-focused outcomes should
be incorporated into trial design.58
Case Vignettes
The following clinical scenarios illustrate some of the
features, diagnostic considerations, and treatment oppor-
tunities discussed in the previous sections.
Case 1
A 4-year-old boy is evaluated for fever. Urinalysis shows
50 to 75 red blood cells per high-power field but urine
culture is negative. Repeat urinalysis several weeks later
again shows hematuria and he is referred to a pediatric
nephrologist. His mother states that she has had blood in
her urine since childhood but has been told that she likely
has a benign disorder. She has not received a specific
diagnosis or genetic counseling. There is no other known
family history of hematuria or kidney disease.
Because of this family history, the family is referred to a
geneticist. The child and his mother are found to have X-
linked Alport syndrome due to a splicing variant in
COL4A5. The mother is referred to her primary provider for
further evaluation and found to have proteinuria (urinary
protein-creatinine ratio of 1.5 mg/mg) and CKD stage 2
with a serum creatinine level of 1.4 mg/dL.
This case illustrates several points:
1. Families with Alport syndrome are often small, making
it difficult to predict inheritance or prognosis from
examination of the family pedigree.
2. Familial hematuria may be undiagnosed or treated due
to misconceptions about its prognosis.
AJKD Vol 77 | Iss 2 | February 2021
Kashtan
3. Lack of a diagnosis can result in a missed opportunity
for early intervention.
Persistent hematuria is the earliest manifestation of a
potentially progressive but treatable nephropathy, Alport
syndrome. Therefore, disease classifications and diagnostic
algorithms should be oriented to early diagnosis and
intervention.
Case 2
A 12-year-old girl is referred to pediatric nephrology for
evaluation of hematuria initially discovered during
evaluation of abdominal pain. Ultrasound of the
abdomen obtained as part of her workup for abdominal
pain did not show urinary tract abnormalities. Family
history for hematuria or kidney disease was negative,
but the family is no longer in contact with the child’s
father. Diagnostic evaluation shows normal blood pres-
sure, estimated GFR, urinary protein excretion, and
serum complement levels.
Urinalyses over the course of the next 6 months show
persistence of hematuria. The pediatric nephrologist elects
to perform a kidney biopsy, which shows no light
microscopic abnormalities and negative routine immuno-
fluorescence studies. Electron microscopy shows uni-
formly thin glomerular basement membranes with an
average width of 190 nm, without duplication, lamella-
tion, or electron-dense deposits. Genetic testing shows a
unique heterozygous missense variant in COL4A3.
This case raises several questions:
1. What is the diagnosis, Alport syndrome or thin base-
ment membrane nephropathy?
2. What should the patient and family be advised
regarding her prognosis?
3. How should she be monitored prospectively?
4. When is intervention appropriate?
Regardless of the name given to this child’s condition,
she has a risk for progression to CKD that is difficult to
precisely predict. A diagnosis of Alport syndrome conveys
the reality of this risk and the need for regular follow-up
by a primary provider or nephrologist. A diagnosis
of Alport syndrome provides her family with sources
of information and support geared to the Alport
community.
Conclusions
It is now clear that a variant in COL4A3, COL4A4, and
COL4A5 is a risk factor for CKD. Whether one thinks of
people with these variants as having a single disease with a
spectrum of phenotypes (Alport syndrome) or as having
distinct disorders (Alport syndrome or thin basement
membrane nephropathy), it is crucial that they have reg-
ular follow-up by a primary provider or nephrologist and
initiation of ACE-inhibitor therapy when appropriate. It is
likewise crucial that clinicians attempt to establish a
definitive diagnosis in people with persistent glomerular
AJKD Vol 77 | Iss 2 | February 2021
hematuria. Individuals diagnosed with Alport syndrome or
found to have COL4A variants should be informed by cli-
nicians about Alport syndrome registries to help further
our understanding of the disease and responses to
intervention.
Article Information
Author’s Affiliation: Pediatric Nephrology, University of Minnesota
Medical School, Minneapolis, MN.
Address for Correspondence: Clifford E. Kashtan, MD, Division of
Pediatric Nephrology, University of Minnesota Medical School, 2450
Riverside Ave, East Building, 6th Floor, MB679, Minneapolis, MN.
55454 E-mail: kasht001@umn.edu
Support: This review was produced without any direct financial
support.
Financial Disclosure: Dr Kashtan is a site investigator for the
CARDINAL trial, sponsored by Reata Pharmaceuticals, and the
HERA trial, sponsored by Sanofi-Genzyme. He has received
research funding from the Novartis Institute for Biomedical
Research; has recent or current consulting relationships with
Daiichi-Sankyo, Ono Pharmaceuticals, and Retrophin; and is the
Executive Director of the Alport Syndrome Treatments and
Outcomes Registry (ASTOR; alportregistry.org), which is
supported by the Alport Syndrome Foundation (alportsyndrome.
org) and private donations. None of the entities listed had a role in
defining the content of this review.
Peer Review: Received January 2, 2020, in response to an invitation
from the journal. Evaluated by 3 external peer reviewers, with direct
editorial input from an Associate Editor and a Deputy Editor.
Accepted in revised form March 24, 2020.
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