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 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 microscopic hematuria in IgAN.

Nephrotic Syndrome

Nephrotic syndrome is uncommon, occurring in only 5% of all patients with IgAN, but it is more common in children and adolescents. Nephrotic-range proteinuria is principally seen in patients with advanced glomerulosclerosis. In those children and adults presenting with concurrent nephrotic syndrome, microscopic 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 an acute, severe immune and inflammatory injury resulting in crescent formation, called crescentic IgAN. This may be the first presentation of the disease or can occur superimposed on known mild IgAN. Alternatively, AKI can occur with mild glomerular injury when heavy glomerular hematuria leads to tubular occlusion by red cell casts. This is a reversible phenomenon, and recovery of kidney function occurs with supportive measures.

Other Presentations

Other presentations of IgAN include hypertension and chronic kidney disease (CKD) where the patient is identified coincidentally.

Light Microscopy

Light microscopic abnormalities may be minimal, but the most common appearance is mesangial hypercellularity ( Fig. 20.1 ). This is most commonly diffuse and global, but focal segmental hypercellularity is also seen. Focal segmental glomerulosclerosis is also described, and crescentic change 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).

Kidney biopsy showing mesangial proliferation (M) and expansion of the mesangial extracellular matrix (S) in a patient with IgA nephropathy. A capsular adhesion can also be seen (arrow) .

Tubulointerstitial changes do not differ from those seen in other forms of progressive GN, reflecting the final common pathway of renal parenchymal 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. 20.2 ). IgA deposition is diffuse and global. In 15% of cases, IgA is the only deposited immunoglobulin. Other immunoglobulins are also frequently detectable (immunoglobulin [Ig]G in 50% to 70%, IgM in 31% to 66%), but their presence does not appear to correlate with clinical outcome. The complement component C3 is also commonly present.

Kidney biopsy showing immunofluorescent staining for mesangial immunoglobulin A (IgA) .

Electron Microscopy

Electron microscopy shows mesangial and paramesangial electron-dense deposits corresponding to IgA immune complexes ( Fig. 20.3 ). 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 experience thinning of the glomerular basement membrane indistinguishable from thin membrane disease. It remains unclear whether the clinical course of these patients is different.

Electron micrograph showing immunoglobulin A immune complex deposition within the mesangium and paramesangium (arrows) . CL, Capillary loops; FP, normal podocyte foot processes.

The Oxford Classification of Immunoglobulin A Nephropathy

The Oxford Classification of IgAN, published in 2009, is an international scoring system for evaluating pathologic features on kidney biopsy. Four variables were identified that correlated most strongly with clinical outcome, independent of known clinical risk factors at the time of diagnosis, including the presence of hypertension, reduced GFR, and degree of proteinuria and proteinuria and blood pressure at follow-up: these included the presence of mesangial hypercellularity (M), segmental glomerulosclerosis (S) and tubular atrophy/interstitial fibrosis (T), and endocapillary hypercellularity (E) ( Table 20.1 ). 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 are 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 Oxford classification, the presence of crescents did not independently predict clinical outcome in IgAN. However, the Oxford study excluded patients with advanced CKD at presentation or 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 2017 addition to the Oxford Classification of crescent scores (MEST-C): C0 (no crescents), C1 (crescents in less than one-fourth of glomeruli), and C2 (crescents in over one-fourth 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.