IGA NEPHROPATHY
IgA nephropathy (IgAN; also known
as Berger disease) is the most common primary glomerular disease world-wide.
IgAN can occur as a primary renal phenomenon or secondary to various extrarenal
conditions, including chronic hepatic disease (especially alcoholic cirrhosis),
celiac disease, HIV, inflammatory bowel disease, and others. In addition, an
identical renal disease may occur as part of the systemic vasculitis seen in
Henoch-Schönlein purpura (see Plate 4-61).
The frequency of IgAN in a renal
biopsy series ranges from 5% to 10% in the United States to 35% in Asian
countries. IgAN may occur at any age but is usually diagnosed in young adults,
with a male : female ratio of at least 2 : 1. The clinical manifestations are
diverse and can include asymptomatic hematuria and proteinuria, gross
hematuria, nephrotic syndrome, and acute kidney injury. In up to one in three
patients, IgAN will progress to end-stage renal disease.
PATHOGENESIS
In IgAN, glomerular injury occurs
when polymeric IgA1 molecules (i.e., two or more IgA1 antibodies joined by a J
chain protein) deposit in the mesangium, resulting in a variable degree of
glomerular hyper- cellularity and sclerosis.
In some patients, primary IgAN
manifests as episodes of gross hematuria within 1 or 2 days of a mucosal
infection. Thus it was once believed that this condition resulted from
overstimulation of the mucosal immune system, which is the main site of IgA
synthesis in normal individuals. Subsequent investigation, however, revealed
that mucosal plasma cells actually have a decreased level of IgA production in
the setting of IgAN. Instead, there is an increased number of active IgA-specific
plasma cells in the systemic circulation and bone marrow. Therefore, although
mucosal infections may precipitate abnormal IgA production, the polymeric IgA1
deposits derive from an abnormal systemic immune response. This process may
reflect a defect in T-cell control of IgA production.
A mere increase in the production
of IgA, however, is still inadequate to explain disease formation. For example,
patients with myeloma or AIDS often have a significant increase in IgA levels
without concomitant IgAN. Instead, it appears that the IgA molecules
responsible for renal disease possess unique features that promote their
accumulation within mesangial cells. In particular, there appears to be a
reduced degree of glycosylation at the hinge region O-glycans, which may reflect
reduced function of the enzyme β-1,3-galatosyl- transferase in IgA-producing B
cells. Recent studies suggest that defective IgA1 glycosylation may be an
inherited risk factor.
These structural changes in the IgA
molecule appear to promote mesangial deposition through multiple mechanisms,
although the details are still unclear. First, the fact that the IgA molecules
are in polymeric form may promote some nonspecific, size-based trapping. Second,
the altered glycosylation appears to increase the affinity for mesangial
extracellular matrix components, such as type IV collagen. Third, it appears
that specific mesangial receptors normally bind to and clear IgA from the
circulation, and that the structural changes in the IgA molecule may interfere
with this process and lead to IgA accumulation. Finally, the modified IgA
molecules also undergo slower systemic clearance, further promoting their
accumulation.
Once IgA binds to the mesangium, it
may stimulate mesangial cell proliferation and trigger mesangial cell release
of proinflammatory mediators, such as interleukin 6 and TNF-α, as well as profibrogenic
mediators, such as PDGF-β and TGF-β. In addition, IgA appears to activate
complement via the alternate pathway and the mannose-binding lectin (MBL)
pathway. In normal circumstances, MBL activates complement when its
carbohydrate recognition domain (CRD) binds to mannose residues on pathogen
surfaces. In IgAN, it is possible that the CRD recognizes the abnormally glycosylated
region of the IgA molecule itself. Finally, IgG may target regions of the IgA
molecule and promote further inflammation.
Not all IgA that binds to the
mesangium, however, is capable of generating disease. In fact, in some series
up to 5% to 15% of otherwise healthy individuals are found to have glomerular
IgA deposition. The specific changes in IgA that allow it to provoke inflammation
after mesangial deposition, as well as the genetic features that underpin these
changes, have not been identified.
Secondary IgAN may reflect either overproduction or reduced clearance of
IgA. The role of abnormal glycosylation has not been adequately studied. The
most common cause of secondary IgAN is chronic liver disease, which causes
reduced IgA clearance. Other conditions, such as celiac disease and HIV
infection, may act by increasing the levels of circulating IgA antibodies. Even
in these settings, a majority of the patients found to have glomerular IgA
deposits have no clinical signs of IgAN, underscoring that IgA-mesangial
interactions are important for triggering pathologic changes.
PRESENTATION AND DIAGNOSIS
The clinical presentation of
primary IgAN is variable. In about half of patients, especially those under 40
years of age, the disease presents as episodes of gross isolated hematuria and
flank pain that occur within a few days of an upper respiratory tract infection
(either bacterial or viral). These episodes are sometimes termed
“synpharyngitic nephritis.” The latency period is shorter than in
poststreptococcal glomerulonephritis (see Plate 4-19), which tends to occur
about 10 days after infection.
In about 40% of patients, and more
commonly in adults, IgAN presents as microscopic hematuria and mild proteinuria
(less than 2 g/day), which is detected on routine urinalysis. In 10% of
patients, the proteinuria is severe enough to cause nephrotic syndrome. About
25% of patients have hypertension at the time of diagnosis, and another 25%
develop hypertension over time. The age-related differences in clinical
features are consistent with the existence of multiple different underlying
pathogenetic mechanisms in IgAN.
In a majority of cases, serum
creatinine and other markers of renal function are normal. In 5% to 10% of
cases, however, acute kidney injury (AKI) occurs, reflecting either tubular
obstruction by erythrocytes or fulminant disease, such as rapidly progressive
glomerulonephritis (see Plate 4-25). AKI is more common in the elderly,
possibly reflecting the higher incidence of coexistent chronic kidney disease in
this population. In most cases, however, the pathologic features of IgAN are
relatively mild, and thus renal insufficiency is not a typical presenting
clinical feature.
Urine microscopy typically shows
dysmorphic RBCs and/or RBC casts, consistent with their glomerular origin.
Serum IgA levels may be elevated in up to 50% of patients. Because complement
activation is mild, serum levels of both complement C3 and C4 are normal,
unlike in postinfectious glomerulonephritis or membranoproliferative
glomerulonephritis.
In the absence of extrarenal
symptoms suggestive of a systemic process, the differential diagnosis of
glomerular hematuria with proteinuria is very broad. For cases with isolated
glomerular hematuria (i.e., without proteinuria), however, the other major
possibilities are thin basement membrane nephropathy and hereditary nephritis
(see Plate 4-26). The likelihood of these inherited disorders can usually be
determined based on a detailed family history. If the urine contains RBCs but
there is no strong evidence of glomerular bleeding, such as dysmorphic cells or
casts, the differential diagnosis should be expanded to include urologic
diseases such as infection, tumor, or calculi especially
if the patient is an adult.
The definitive diagnostic test for
IgAN is renal biopsy; however, the specific indications for this procedure
vary in different countries. In the
United States, biopsy is generally reserved for cases with at least mild
proteinuria (<1 g/day) and/or renal insufficiency in addition
to hematuria.
Mild to moderate mesangial
hypercellularity is typically seen using light microscopy. A subset of cases
feature endocapillary hypercellularity, which can be segmental or global, focal
or diffuse, and with or without sclerosing lesions. Proliferation and sclerosis
often coexist in the same biopsy, which suggests that proliferative lesions
lead to scarring and sclerosis.
Extracapillary cellular crescents
(see Plate 4-25) may occur if there is diffuse endocapillary hypercellularity,
but these rarely involve more than 50% of glomeruli. IgA immune deposits may be
seen in the mesangium and, in cases with endocapillary proliferation, the
subendothelium.
The degree of tubular atrophy and
interstitial fibrosis generally reflects the degree of glomerular scarring.
Tubules may contain intraluminal RBCs. In cases of severe hematuria, the RBCs
may cause tubular obstruction with subsequent tubular injury. In cases with long-standing hematuria, tubules may show
hemosiderin granules. If there is hypertension, arterial vessels typically show
a proportionate degree of mild to moderate medial sclerosis and intimal
fibrosis. True vasculitis, however, is rare and suggests the alternative
diagnosis of Henoch-Schönlein purpura.
On immunofluorescence (IF)
microscopy, granular mesangial IgA deposits are seen; dominant or codominant
IgA deposition is diagnostic of IgAN. A variable degree of subendothelial
deposition may also be seen, which correlates with the degree of endocapillary
hypercellularity. IgG and IgM deposits are present in up to 50% of IgAN
biopsies, but their staining intensity should not exceed that of IgA. C3
deposits are usually present but C1q staining is typically absent.
Electron microscopy demonstrates
electron dense deposits at sites corresponding to the IF staining pattern,
which is typically mesangial and, less commonly, subendothelial. Endothelial
tubulo-reticular inclusions should not be present because they suggest the
alternate diagnosis of lupus nephritis. Podocyte foot process effacement is
usually focal and confined to capillary loops that have either sclerosis or
endocapillary hypercellularity (and subendothelial deposits). The finding of
diffuse (>50%) foot process effacement in a majority of
capillary loops, without accompanying subendothelial deposits, is seen in cases
of IgAN with coexistent minimal change disease (MCD).
The pathologic findings of dominant
or co-dominant IgA glomerular staining are identical to those seen in renal
biopsies of patients with Henoch-Schönlein purpura (HSP, see Plate 4-61). IgAN
and HSP are thus distinguished based on the presence or absence of extra renal
disease. HSP is a multisystem vasculitis affecting small vessels of the skin,
gut, and kidney. Purpura occurs in all cases, whereas arthritis/arthralgias,
abdominal pain, and/or renal involvement occur in a subset.
TREATMENT
No specific therapy is indicated for
those with isolated hematuria. Instead, such patients should be closely
monitored for the development of hypertension, proteinuria, or renal
insufficiency.
In contrast, all patients with
proteinuria should be started on an ACE inhibitor or ARB, regardless of blood
pressure level, because of their antiproteinuric effect. High-dose fish oil
supplements may also help reduce proteinuria and slow the progression of
disease in patients with proteinuria >1 g/day and renal insufficiency; however,
their effects have been inconsistent in clinical trials.
Patients with persistent
proteinuria (typically >1 g/ day) are typically candidates for
immunosuppression with steroids. A typical 6-month regimen uses pulse methylprednisolone
for 3 days during months 0, 3, and 6, with daily oral prednisone for all 6
months. For those patients with rapidly progressive glomerulonephritis and
extensive crescent formation, the administration of steroids and
cyclophosphamide may improve prognosis. The benefit of other agents, such as
cyclosporine and mycophenolate mofetil, has not been proven.
PROGNOSIS
The rate of progression is
typically slow, with about half of patient progressing to ESRD within 20 years
of diagnosis.
The clinical features associated
with worse outcomes include persistent proteinuria (>1
g/day), elevated serum creatinine concentration at diagnosis, and poorly
controlled hypertension.
The pathologic features associated
with worse out-comes include moderate to severe mesangial hypercellularity, the
presence of endocapillary hypercellularity, segmental sclerosis, and tubular
atrophy/interstitial fibrosis affecting more than 25% of the cortical area.
Similarly, the presence of extensive cellular crescent formation portends worse
outcomes.
Although IgA deposition recurs in
up to 50% of renal allograft recipients, this is usually an isolated
immunohistochemical finding, without significant glomerular hypercellularity or
clinical signs of disease (e.g., hematuria and proteinuria). Graft loss from
recurrent IgAN is rare.
Compared with primary IgAN,
secondary IgAN appears to have a lower rate of progression to end-stage renal
disease. In most cases, the clinical course is dominated by the underlying
disease (e.g., alcoholic cirrhosis).
