Disease of the kidney
Medical condition
IgA nephropathy
(
IgAN
), also known as
Berger's disease
(
) (and variations), or
synpharyngitic glomerulonephritis
, is a
disease of the kidney
(or nephropathy) and the
immune system
; specifically it is a form of
glomerulonephritis
or an
inflammation
of the
glomeruli
of the
kidney
. Aggressive Berger's disease (a rarer form of the disease) can attack other major organs, such as the
liver
,
skin
and
heart
.
IgA nephropathy is the most common glomerulonephritis worldwide; the global incidence is 2.5/100,000 per year amongst adults.
[1]
Aggressive Berger's disease is on the
NORD
list of rare diseases.
[2]
Primary IgA nephropathy is characterized by deposition of the
IgA
antibody
in the glomerulus. There are other diseases associated with glomerular IgA deposits, the most common being
IgA vasculitis
(formerly known as
Henoch?Schonlein purpura
[HSP]), which is considered by many to be a systemic form of IgA nephropathy.
[3]
IgA vasculitis presents with a characteristic
purpuric
skin rash,
arthritis
, and abdominal pain, and occurs more commonly in children. HSP is associated with a more benign prognosis than IgA nephropathy. In non-aggressive IgA nephropathy there is traditionally a slow progression to chronic kidney failure in 25?30% of cases during a period of 20 years.
Signs and symptoms
[
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]
The classic presentation for the non-aggressive form (in 40?50% of the cases) is episodic
hematuria
, which usually starts within a day or two of a non-specific
upper respiratory tract infection
(hence
synpharyngitic
), as opposed to
post-streptococcal glomerulonephritis
, which occurs some time (weeks) after initial infection. With both aggressive and non-aggressive Berger's disease
loin pain
can also occur. The gross hematuria may resolve after a few days, though
microscopic hematuria
will persist, it is however more common with aggressive Berger's disease for gross hematuria to persist rather than microscopic hematuria. Renal function usually remains normal with non-aggressive Berger's disease, though rarely
acute kidney failure
may occur (see below). This presentation is more common in younger adults.
[
citation needed
]
A smaller proportion (20?30%), usually the older population, have microscopic hematuria and
proteinuria
(less than 2 gram/day). These patients may be asymptomatic and only picked up due to urinalysis. Hence, the disease is more commonly diagnosed in situations where screening of urine is compulsory (e.g., schoolchildren in
Japan
).
[
citation needed
]
Very rarely (5% each), the presenting history is:
[
citation needed
]
A variety of systemic diseases are associated with aggressive IgA nephropathy (Berger's disease) such as
liver failure
,
cancer
,
celiac disease
,
systemic lupus erythematosus
,
rheumatoid arthritis
,
heart failure
,
reactive arthritis
,
ankylosing spondylitis
and
HIV
. Diagnosis of Berger's disease and a search for any associated disease occasionally reveals such an underlying serious systemic disease. Occasionally, there are simultaneous symptoms of
Henoch?Schonlein purpura
; see below for more details on the association. Some HLA alleles have been suspected along with complement phenotypes as being genetic factors. Non-aggressive Berger's disease may also be associated with any of the above systemic diseases, however, this is rare.
[
citation needed
]
Morphology
[
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]
Histologically, IgA nephropathy may show mesangial widening and focal and segmental inflammation. Diffuse mesangial proliferation or crescentic glomerulonephritis may also be present. Immunofluorescence shows mesangial deposition of IgA often with
C3
and
properdin
and smaller amounts of other immunoglobulins (
IgG
or
IgM
). Early components of the
classical complement pathway
(
C1q
or
C4
) are usually not seen. Electron microscopy confirms electron-dense deposits in the mesangium that may extend to the subendothelial area of adjacent capillary walls in a small subset of cases, usually those with focal proliferation.
[
citation needed
]
Pathophysiology
[
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]
Immunostaining
showing IgA in the
glomerulus
of a patient with Henoch-Schonlein
nephritis
.
The pathophysiology, signs and symptoms, and treatment of IgA nephropathy.
The disease derives its name from deposits of
immunoglobulin A
(IgA) in a granular pattern in the mesangium (by
immunofluorescence
), a region of the renal
glomerulus
. The mesangium by light microscopy may be hypercellular and show increased deposition of
extracellular matrix
proteins. In terms of the renal manifestation of
Henoch?Schonlein purpura
, it has been found that although it shares the same histological spectrum as IgA nephropathy, a greater frequency of severe lesions such as glomerular necrosis and crescents were observed. Correspondingly, HSP nephritis has a higher frequency of glomerular staining for fibrin compared with IgAN, but with an otherwise similar immunofluorescence profile.
[4]
There is no clear known explanation for the accumulation of the IgA. Exogenous
antigens
for IgA have not been identified in the kidney, but it is possible that this antigen has been cleared before the disease manifests itself. It has also been proposed that IgA itself may be the antigen.
[
citation needed
]
A recently advanced theory focuses on abnormalities of the IgA1 molecule. IgA1 is one of the two immunoglobulin subclasses (the other is IgD) that is
O-glycosylated
on a number of
serine
and
threonine
residues in a special
proline
-rich hinge region. Aberrant glycosylation of IgA appears to lead to
polymerisation
of the IgA molecules in tissues, especially the glomerular mesangium.
[5]
A similar mechanism has been claimed to underlie
Henoch?Schonlein purpura
, a
vasculitis
that mainly affects children and can feature renal involvement that is almost indistinguishable from IgA nephritis. However, human studies have found that degalactosylation of IgA1 occurs in patients with IgA nephropathy in response only to gut antigen exposures (not systemic), and occurs in healthy people to a lesser extent.
[6]
This strongly suggests degalactosylation of IgA1 is a result of an underlying phenomenon (abnormal mucosal antigen handling) and not the ultimate cause of IgA nephropathy. Prevailing evidence suggests that both galactose-deficient o-glycans in the hinge region of IgA1 and synthesis and binding of antibodies against IgA1 are required for immunoglobulin complexes to form and accumulate in glomeruli.
[7]
From the fact that IgAN can recur after renal transplant, it can be postulated that the disease is caused by a problem in the
immune system
rather than the kidney itself. Remarkably, the IgA1 that accumulates in the kidney does not appear to originate from the mucosa-associated lymphoid tissue (MALT), which is the site of most upper respiratory tract infections, but from the
bone marrow
. This, too, suggests an immune pathology rather than direct interference by outside agents.
[8]
[9]
Natural history
[
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]
Since IgA nephropathy commonly presents without symptoms through abnormal findings on
urinalysis
, there is considerable possibility for variation in any population studied depending upon the
screening
policy. Similarly, the local policy for performing kidney
biopsy
assumes a critical role; if it is a policy to simply observe patients with isolated
bloody urine
, a group with a generally favourable
prognosis
will be excluded. If, in contrast, all such patients are biopsied, then the group with isolated
microscopic hematuria
and isolated mesangial IgA will be included and improve the prognosis of that particular series.
[
citation needed
]
Nevertheless, IgA nephropathy, which was initially thought to be a benign disease, has been shown to not be a benign disease, particularly if the patient presents with an aggressive form. Though most reports describe Berger's disease as having an indolent evolution towards either healing or renal damage, a more aggressive course is occasionally seen associated with extensive crescents, and presenting as
acute kidney failure
. In general, the entry into
chronic kidney failure
is slow as compared to most other glomerulonephritides ? occurring over a time scale of 30 years or more (in contrast to the 5 to 15 years in other glomerulonephritides), however, in aggressive Berger's disease the time scale is within 5?10 years and often sooner. This may reflect the earlier diagnosis made due to frank hematuria.
[
citation needed
]
Complete
remission
of aggressive Berger's disease rarely occurs in adults. In about 5% of cases, however, there is a higher chance of remission with non-aggressive Berger's disease (this is estimated to be around 7.4% of cases). There is a high chance of relapse, particularly with aggressive Berger's disease. However, given the evolution of this disease, the longer term (10?20 years) outcome of such patients is not yet established.
[
citation needed
]
Overall, the current 10-year survival rate for aggressive Berger's disease is 25% and 73% for non-aggressive Berger's disease.
[
citation needed
]
Diagnosis
[
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]
For an adult patient with isolated
hematuria
, tests such as
ultrasound
of the kidney and
cystoscopy
are usually done first to pinpoint the source of the
bleeding
. These tests would rule out
kidney stones
and
bladder cancer
, two other common
urological
causes of hematuria. In children and younger adults, the history and association with respiratory infection can raise the suspicion of IgA nephropathy. A kidney
biopsy
is necessary to confirm the diagnosis. The biopsy specimen shows proliferation of the
mesangium
, with IgA deposits on
immunofluorescence
and
electron microscopy
. However, patients with isolated
microscopic hematuria
(i.e. without associated proteinuria and with normal
kidney function
) are not usually biopsied since this is associated with an excellent
prognosis
. A
urinalysis
will show
red blood cells
, usually as red cell
urinary casts
.
Proteinuria
, usually less than 2 grams per day, also may be present. Other
renal
causes of isolated hematuria include
thin basement membrane disease
and
Alport syndrome
, the latter being a
hereditary disease
associated with
hearing impairment
and eye problems.
[
citation needed
]
Other
blood tests
done to aid in the diagnosis include
CRP
or
ESR
,
complement
levels,
ANA
, and
LDH
.
Protein electrophoresis
and
immunoglobulin
levels can show increased IgA in 50% of all patients.
[
citation needed
]
Treatment
[
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]
The ideal treatment for IgAN would remove IgA from the glomerulus and prevent further IgA deposition. This goal still remains a remote prospect. There are a few additional caveats that have to be considered while treating IgA nephropathy. IgA nephropathy has a very variable course, ranging from a benign recurrent
hematuria
up to a rapid progression to
chronic kidney failure
and failure of other major organs. Hence the decision on which patients to treat should be based on the prognostic factors and the risk of progression. Also, IgA nephropathy recurs in
transplants
despite the use of
ciclosporin
,
azathioprine
or
mycophenolate mofetil
,
cyclophosphamide
,
Isotretinoin
and
steroids
in these patients. There are persisting uncertainties, due to the limited number of patients included in the few controlled, randomized, studies performed to date. These studies hardly produce statistically-significant evidence regarding the heterogeneity of IgA nephropathy patients, the diversity of study treatment protocols, and the length of follow-up.
[
citation needed
]
In cases where
tonsillitis
is the precipitating factor for episodic hematuria, a
tonsillectomy
has been claimed to reduce the frequency of those episodes. However, it does not reduce the incidence of progressive
kidney failure
.
[10]
Dietary
gluten
restriction, used to reduce mucosal
antigen
challenge, also has not been shown to preserve
kidney function
.
Phenytoin
has also been tried without any benefit.
[11]
A subset of IgA nephropathy patients, who have
minimal change disease
on light
microscopy
and clinically have
nephrotic syndrome
, show an exquisite response to
steroids
, behaving more or less like
minimal change disease
. In other patients, the evidence for steroids is not compelling. Short courses of high dose steroids have been proven to lack benefit. However, in patients with aggressive Berger's disease 6 months regimen of steroids in addition to other medications may lessen proteinuria and preserve renal function.
[12]
The study had 10 years of patient follow-up data, and did show a benefit for steroid therapy; there was a lower chance of reaching end-stage renal disease (renal function so poor that dialysis was required) in the steroid group. Importantly, angiotensin-converting enzyme inhibitors were used in both groups equally.
[
citation needed
]
Cyclophosphamide
(traded as
endoxan
&
cytoxan
) and
Isotretinoin
have commonly been used, often with
anti-platelet
/
anticoagulants
in patients with Aggressive Berger's disease, however, the side effect profile of these drugs, including long term risk of
malignancy
and
sterility
, made them an unfavorable choice for use in young adults. However, one recent study, in a carefully selected high risk population of patients with declining
GFR
, showed that a combination of steroids and
cyclophosphamide
for the initial 3 months followed by
azathioprine
for a minimum of 2 years resulted in a significant preservation of renal function.
[13]
Other agents such as
mycophenolate mofetil
,
ciclosporin
and
mizoribine
have also been tried with varying results.
A study from Mayo Clinic did show that long-term treatment with
omega-3 fatty acids
results in slight reduction of progression to
kidney failure
, without, however, reducing
proteinuria
in a subset of patients with high risk of worsening
kidney function
.
[14]
However, these results have not been reproduced by other study groups and in two subsequent meta-analyses.
[15]
[16]
However, fish oil therapy does not have the drawbacks of
immunosuppressive therapy
. Also, apart from its unpleasant taste and abdominal discomfort, it is relatively safe to consume.
[
citation needed
]
The events that tend to progressive kidney failure are not unique to IgA nephropathy and non-specific measures to reduce the same would be equally useful. These include a low-protein diet and optimal control of
blood pressure
. The choice of the
antihypertensive
agent is open as long as the blood pressure is controlled to desired level. However,
Angiotensin converting enzyme inhibitors
and
Angiotensin II receptor antagonists
are favoured due to their anti-proteinuric effect.
[
citation needed
]
In December 2021,
budesonide
(Tarpeyo) was approved for medical use in the US to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid disease progression.
[17]
Prognosis
[
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]
Male sex,
proteinuria
(especially > 2 g/day),
hypertension
,
smoking
,
hyperlipidemia
, older age, familial disease and elevated
creatinine
concentrations are markers of a poor outcome. Frank
hematuria
has shown discordant results with most studies showing a better prognosis, perhaps related to the early diagnosis, except for one group which reported a poorer prognosis.
Proteinuria
and
hypertension
are the most powerful prognostic factors in this group.
[18]
There are certain other features on kidney
biopsy
such as interstitial scarring which are associated with a poor prognosis. ACE gene
polymorphism
has been recently shown to have an impact with the DD
genotype
associated more commonly with progression to
kidney failure
.
[
citation needed
]
Disease progression in IgAN can be predicted at the time of
kidney biopsy
by a risk-prediction tool.
[19]
Epidemiology
[
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]
Men are affected three times as often as women. There is also marked geographic variation in the prevalence of IgA nephropathy throughout the world. It is the most common glomerular disease in the
Far East
and
Southeast Asia
, accounting for almost half of all the patients with glomerular disease.
[
citation needed
]
However, it accounts for only about 25% of the proportion in Europeans and about 10% among North Americans, with African?Americans having a very low prevalence of about 2%.
[
citation needed
]
A confounding factor in this analysis is the existing policy of
screening
and use of kidney
biopsy
as an investigative tool. School children in
Japan
undergo routine
urinalysis
(as do army recruits in
Singapore
) and any suspicious abnormality is pursued with a kidney biopsy, which might partly explain the high observed
incidence
of IgA nephropathy in those countries.
[
citation needed
]
Genetics
[
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]
Though various associations have been described, no consistent pattern pointing to a single susceptible gene has been identified to date. Associations described include those with C4 null allele, factor B Bf alleles, MHC antigens and IgA isotypes. ACE
gene
polymorphism
(D allele) is associated with progression of kidney failure, similar to its association with other causes of
chronic kidney failure
. However, more than 90% of cases of IgA nephropathy are sporadic, with a few large pedigrees described from
Kentucky
and
Italy
(
Online Mendelian Inheritance in Man
(OMIM):
161950
).
[
citation needed
]
History
[
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]
Dr Jean Berger
William Heberden
, the elder, first described the disease in 1801 in a 5-year-old child with abdominal pain,
hematuria
,
hematochezia
, and purpura of the legs.
[20]
In 1837,
Johann Lukas Schonlein
described a syndrome of purpura associated with joint pain and urinary precipitates in children.
Eduard Heinrich Henoch
, a student of Schonlein's, further associated abdominal pain and renal involvement with the syndrome.
[
citation needed
]
In 1968, Jean Berger (1930?2011), a pioneering French
nephrologist
, with co-author, the electron microscopist Nicole Hinglais, was the first to describe IgA deposition in this form of
glomerulonephritis
and therefore it is sometimes called Berger's disease.
[21]
References
[
edit
]
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External links
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Classification
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