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.
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.
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.
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).