Immunoglobulin a nephropathy and Henoch–Schönlein disease

1. What is immunoglobulin a nephropathy (IGAN)?

IgAN is a glomerular disease characterized by the deposition of type A immunoglobulin in the mesangial areas of the glomerulus. This leads to inflammation and damage to the glomerulus and the surrounding structures. Originally known as Berger disease, IgAN is the most common biopsy-proven primary glomerular disease.

2. What are the typical biopsy findings in IGAN?

On light microscopy (LM), mesangial cellular proliferation and matrix expansion are the classic findings. In cases with rapid deterioration in kidney function, diffuse proliferation of both the mesangial and endocapillary cells can be appreciated, in association with segmental necrosis and crescents. Nonspecific pathologic features associated with advanced glomerular diseases in general can be seen in IgAN, including glomerulosclerosis, tubular atrophy, and interstitial fibrosis.

On immunofluorescence (IF), the defining feature of IgAN is the presence of prominent IgA deposits within the mesangium in a dominant or codominant intensity with IgG and more rarely IgM.

On electron microscopy (EM), electron-dense mesangial deposits are the typical finding. Paramesangial and subendothelial extension of the deposits may be present but are less common.

3. What is the pathogenesis of IGAN?

A unifying theory of the pathogenesis has not been fully elucidated. The available data suggest that tissue injury can be initiated by the deposition of abnormally underglycosylated IgA subclass 1 (IgA1) immune complexes in the mesangium. These complexes somehow trigger mesangial cell activation, which in turn releases proinflammatory cytokines and profibrotic mediators, affecting nearby glomerular structures. It is also suggested that IgA deposits activate the local complement system. The higher C3 deposition compared with C1q suggests that the lectin and alternative complement pathways are implicated.

4. What is the etiology of IGAN?

The etiology of IgAN is unknown in the majority of cases. There appears to be a dysregulation of the mucosal-type IgA immune response that results in the production of the aberrant IgA1. The aberrant IgA1 forms immune complexes that deposit in the glomerulus, although the specific relationship between the complexes glomerular deposition and injury remain incompletely understood. It is likely that there are contributions from both genetic and environmental factors that cause the production of aberrant IgA1.

In familial IgAN, genetic linkage studies have suggested some specific genetic abnormalities. Most of the reported kindreds with IgAN are inherited in an autosomal-dominant pattern with incomplete penetrance. Genomewide association studies that include populations of IgAN from across the world have identified associated variants in the HLA gene family. Associations have described abnormalities within 1q32 that contains multiple complement regulatory genes as a possible IgAN susceptibility locus. In most cases, especially the more common sporadic variants, additional environmental factors are necessary to produce the clinical phenotype.

5. Is IGAN associated with any other conditions?

Yes. Although IgAN is most commonly a primary (idiopathic) disorder, there are some well-established associations. The most common are

• Liver cirrhosis (both alcohol- and virus-induced)

• Celiac disease

• HIV infection

• Inflammatory bowel disease

• Some rheumatic conditions

IgAN has also been described in association with

• Minimal change disease (MCD)

• Membranous nephropathy

• Antineutrophil cytoplasmic antibody-positive vasculitis

There is increased recognition of IgA deposition with Staphylococcus -related glomerulonephritis (GN). However, unlike primary IgAN, the presence of the active infection and typical large subepithelial deposits (humps) on microscopy can help distinguish between these two entities.

6. How does IGAN present?

About 20% to 30% of patients present with recurrent gross hematuria, typically within a few days of an upper respiratory infection. Classically known as “synpharyngetic hematuria,” this presentation is much more common in children and young adults than in the older population. Dull flank pain and low-grade fever may be present, and this pattern can mimic both urinary tract infection and urolithiasis.

The majority of the remaining patients with IgAN are asymptomatic at presentation and are detected on routine examination of the urine (positive for microscopic hematuria with or without mild proteinuria [<500 mg/day]). Systemic hypertension may also be found. Nephrotic-range proteinuria or lesser degrees of proteinuria without hematuria are unusual but also occur. In less than 5% of patients, IgAN can present with acute kidney injury. It is felt that the kidney injury is most commonly secondary to tubular obstruction and/or damage by red cell casts, which form in the course of the gross hematuria. Crescentic GN in IgAN can also produce a similar clinical phenotype and should be considered whenever an acute deterioration of kidney function occurs. Because this is a relatively rare clinical presentation, a kidney biopsy should be obtained to differentiate acute tubular damage from crescentic GN. This is particularly important given that their outcome and management are so distinctly different.

At least 20% of patients with IgAN present with chronic kidney disease as a result of long-standing but undiagnosed disease. The clinical phenotype usually includes hypertension, mild to moderate proteinuria, and hematuria of undetermined duration in combination with varying degrees of chronic kidney disease.