Immunoglobulin A Nephropathy and Related Disorders

Episodic Visible Hematuria

Episodic visible hematuria most frequently occurs in the second or third decades of life and is the presenting complaint in 40% to 50% of patients. The urine is usually brown rather than red and will often be described by the patient as looking like “tea without milk” or “cola-colored.” The passage of clots is very unusual. There may be bilateral loin pain accompanying these episodes, which may be due to renal capsular swelling. Hematuria usually follows intercurrent mucosal infection, most commonly in the upper respiratory tract, but it is occasionally seen following gastrointestinal infection and may be provoked by heavy physical exercise. Spontaneous episodes occur as well. The time course is characteristic, with hematuria appearing within 24 hours of the onset of the symptoms of infection. This differentiates it from the 2- to 3-week delay between infection and subsequent hematuria characteristic of poststreptococcal GN. Visible hematuria resolves spontaneously over a few days in nearly all cases, but nonvisible (microscopic) hematuria may persist between attacks. Most patients only experience a few episodes of visible hematuria, and such episodes typically recur for a few years at most. These episodes are infrequently associated with acute kidney injury (AKI).

Asymptomatic Nonvisible (Microscopic) Hematuria

Asymptomatic nonvisible hematuria is usually detected during routine health screening and identifies 30% to 40% of patients with IgAN in most series. Hematuria may occur alone or with proteinuria. It is rare for proteinuria to occur without hematuria in IgAN.

Nephrotic Syndrome

Nephrotic syndrome is uncommon, occurring in fewer than 5% of patients with IgAN, but it is more common in children and adolescents. Nephrotic-range proteinuria is principally seen in patients with advanced glomerulosclerosis. In children and adults presenting with concurrent nephrotic syndrome, nonvisible hematuria, and mesangial IgA deposition, one should always consider the possibility of the coincidence of the two most common glomerular diseases of young adults: minimal change disease and IgAN. A number of case series have reported patients who, on kidney biopsy, have normal light microscopy, foot process effacement on electron microscopy, and electron-dense mesangial IgA deposits and in whom proteinuria resolved completely in response to corticosteroid therapy. Typically, in these cases, following resolution of proteinuria, both nonvisible hematuria and IgA deposits persist.

Acute Kidney Injury

AKI is uncommon in IgAN (less than 5% of all cases) and develops by two distinct mechanisms. The first is in association with heavy visible glomerular hematuria, which leads to tubular occlusion by red cell casts. This is a reversible phenomenon and recovery of kidney function occurs with supportive measures. The second is a rapidly progressive GN (RPGN) associated with a nephritic presentation and kidney biopsy that shows acute, severe immune and inflammatory injury with fibrinoid necrosis and crescent formation. This may be the initial presentation of the disease or can occur superimposed on known mild IgAN.

Other Presentations

Other presentations of IgAN include hypertension, very occasionally malignant hypertension, and chronic kidney disease (CKD).

Light Microscopy

Light microscopic abnormalities may be minimal, but the most frequent finding is mesangial hypercellularity ( Fig. 21.1 ). This is most commonly diffuse and global, but focal segmental hypercellularity is also seen. Focal segmental glomerulosclerosis is also described, and crescents may be superimposed on diffuse mesangial proliferation with or without associated segmental necrosis. Crescents are a common finding in biopsies performed during episodes of visible hematuria with reduced glomerular filtration rate (GFR).

Tubulointerstitial changes do not differ from those seen in other forms of progressive GN, reflecting the final common pathway of parenchymal kidney disease. Mononuclear cell infiltration is associated with tubular atrophy and interstitial fibrosis, ultimately leading to a widening of the cortical interstitium. This finding correlates with a poor prognosis.

Immunohistology

The presence of dominant or codominant IgA deposits in the mesangium is the defining feature of IgAN. This is detected in kidney biopsy specimens by immunofluorescence or immunohistochemistry ( Fig. 21.2 ). IgA deposition is diffuse and global. In 15% of cases, IgA is the only deposited immunoglobulin. Other immunoglobulins are also frequently detectable (IgG in 50% to 70%, IgM in 31% to 66%), but their presence does not appear to correlate with clinical outcomes. The complement component C3 is commonly present, but C1q staining is almost universally absent, arguing against a role for the classical pathway in IgAN. However, there is evidence for both lectin and alternative pathway activation in IgAN, and activation of both pathways has been associated with a worse prognosis.

Electron Microscopy

Electron microscopy shows mesangial and paramesangial electron-dense deposits corresponding to IgA immune complexes ( Fig. 21.3 ). The size, shape, quantity, and density of the deposits vary between glomeruli. Glomerular capillary wall deposits may also be seen in the subepithelial or, more commonly, subendothelial space. Capillary loop deposits are associated with disease that is more severe. Glomerular basement membrane abnormalities are seen in 15% to 40% of cases and are associated with heavy proteinuria, more severe glomerular changes, and crescent formation. A group of patients have thinning of the glomerular basement membrane indistinguishable from thin membrane disease. It is unclear whether the clinical course of these patients is different.

The Oxford Classification of IgAN

The Oxford Classification, published in 2009, is an international scoring system for evaluating pathologic features of IgAN on kidney biopsy. Four variables were identified that correlated most strongly with clinical outcome, independent of known clinical indicators of disease severity at the time of diagnosis, including the presence of hypertension, reduced GFR, and degree of proteinuria. These four variables included the presence of mesangial hypercellularity (M), segmental glomerulosclerosis (S) and tubular atrophy/interstitial fibrosis (T), and endocapillary hypercellularity (E) ( Table 21.1 ). The first three of these (M, S, and T) were independent predictors of rate of GFR decline and the composite of kidney failure or a 50% decline in GFR. A similar association was seen with endocapillary hypercellularity (E) in patients who had not received immunosuppression; this difference was not observed in patients who received immunosuppression, suggesting that endocapillary lesions may be responsive to immunosuppressive treatment. The presence of multiple pathologic features (M, E, S, and/or T) in combination results in additive risk of kidney disease progression. Among the four predictors, studies have consistently demonstrated that the degree of interstitial fibrosis/tubular atrophy is the strongest predictor of kidney survival. The predictive value of these biopsy features was similar in both adults and children. Since its publication, the Oxford Classification of IgAN has been validated in different patient populations from North America, Europe, and Asia, and it is now widely accepted as the histopathologic scoring system of choice for IgAN.

In the original 2009 Oxford Classification, the presence of crescents did not independently predict clinical outcomes in IgAN. However, the Oxford study excluded patients with advanced CKD at presentation as well as those with rapid progression to kidney failure. A working subgroup of the IgAN Classification Working Group subsequently demonstrated that crescents were independent predictors of kidney outcomes in a pooled cohort of 3096 patients, leading to the 2016 addition to the Oxford Classification of a crescent score (MEST-C): C0 (no crescents), C1 (crescents in less than 25% of glomeruli), and C2 (crescents in over 25% of glomeruli). A score of C1 identifies a group of patients with significantly higher risk of poor kidney outcomes if not treated with immunosuppression, although outcomes were similar to C0 if these patients were treated with immunosuppressive therapy. Notably, these observational data are not sufficient to extrapolate to a recommendation that those with C1 lesions should be treated with immunosuppression. A score of C2 identifies patients at risk of a poor kidney outcome even if treated with immunosuppression.

Immunoglobulin A in IgAN

In humans, IgA is the most abundant antibody. It is predominantly present at mucosal surfaces and in secretions such as saliva and tears, where it protects against mucosal pathogens. The IgA molecule exists as two isoforms, IgA1 and IgA2, with each existing as monomers (single molecules) or polymers (most commonly dimeric IgA). It is predominantly polymeric IgA1 that is found in mesangial IgA deposits in IgAN. The major difference between IgA1 and IgA2 is that IgA1 includes a hinge region that carries a variable complement of O -linked carbohydrates ( Fig. 21.4 ). Changes in the composition of these O -linked sugars is the most consistent finding in patients with IgAN across the world, with identical changes seen in patient cohorts from North America, Europe, and Asia.

The key change is an increase in the serum of IgA1 O -glycoforms that contain less galactose. This increase in poorly O -galactosylated IgA1 O -glycoforms is believed to play a central role in the pathogenesis of IgAN. Poorly O -galactosylated IgA1 O -glycoforms form high-molecular-weight circulating immune complexes, either through self-aggregation, aggregation with soluble CD89, or through the generation of IgG and IgA hinge region-specific autoantibodies (“antiglycan” antibodies). These high-molecular-weight immune complexes are prone to mesangial deposition, resulting ultimately in mesangial cell proliferation, release of proinflammatory mediators, and glomerular injury.

Origins of Mesangial Immunoglobulin A

Many of the features of mesangial IgA are those typically seen in IgA secreted at mucosal surfaces. Mucosal IgA is polymeric, low affinity, and poorly O -galactosylated and is found at increased concentrations in the serum in IgAN. In addition, a number of studies report elevated levels of IgA antibodies specific for food antigens, mucosal vaccines, and gut-associated bacteria in the serum in IgAN. There are also intriguing data suggesting that gut bacteria may themselves be capable of modulating IgA class switching, the amount of mucosal IgA production, and IgA1 O -galactosylation in the gut-associated lymphoid tissue through activation of lymphoid toll-like receptors. Additionally, pathway analysis based on a large meta-analysis of genome-wide association studies identified the intestinal immune network for IgA production as the most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway in IgAN. Most of the identified risk alleles are either directly associated with risk of inflammatory bowel disease or maintenance of the intestinal epithelial barrier, as well as response to mucosal pathogens. These genetic observations are also entirely consistent with known secondary causes of IgAN, which include a range of gastrointestinal disorders including inflammatory bowel disease and celiac disease.