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.

7. What is the differential diagnosis of synpharyngitic hematuria?

The onset of hematuria shortly after a respiratory infection is common to both IgAN and poststreptococcal GN. However, the latent period from infection to gross hematuria averages 1 to 3 days in IgAN versus 10 to 14 days in poststreptococcal GN. Poststreptococcal GN can also be distinguished from IgAN by the presence of hypocomplementemia, which is rarely seen in IgAN, and the elevation of antistreptococcal antibodies in the early phase of infection.

8. How is the IGAN diagnosis established?

Even if IgAN is suspected on the basis of the clinical and laboratory findings, the diagnosis can be confirmed only by the findings on kidney biopsy. The presence of mesangial proliferation and matrix expansion on LM with dominant or codominant deposition of IgA and complement on IF microscopy confirms the diagnosis.

9. Are there any biomarkers to diagnose IGAN or monitor the activity of the disease?

Not yet. Although increased levels of serum IgA can be found in up to 50% of cases, this finding is not specific and has no diagnostic or prognostic value. Alternative biomarkers have been identified, including serum galactose-deficient IgA1 (GD IgA1) and GD IgA1 antibodies and immune complexes, but their utility in routine clinical practice has not been established.

10. Should a kidney biopsy always be performed?

No. Asymptomatic patients with isolated hematuria or mild proteinuria (<500 mg/day) usually follow a benign course. General interventions known to slow progression that are used in other cases of chronic kidney disease should be implemented. Given that histologic findings at this stage of disease are not likely to alter therapy and considering the risk, a kidney biopsy is not warranted. The decision to perform a biopsy in these cases even when IgAN is highly suspected is a matter of debate. Although biopsy can at least confirm the diagnosis, this decision varies widely among nephrologists and the affected patients as well as by geographic region.

Regardless of whether a kidney biopsy is performed, ongoing follow-up of these patients is imperative, because a more concerning phenotype may evolve at any time and is unpredictable. Kidney biopsy is generally recommended in patients with an unexplained serum creatinine above normal for age and sex and/or proteinuria > 500 to 1000 mg/day.

11. What is the prognosis of IGAN?

Most patients who present with isolated hematuria and no proteinuria have a low risk of progression provided these laboratory features do not change. Among patients who develop significant persistent proteinuria > 500 to 1000 mg/day, approximately 25% to 30% will require renal replacement therapy (RRT) within 20 to 25 years of presentation. A higher percentage will require RRT if they have persistent higher-grade proteinuria of more than 2000-3000 mg/day with or without hypertension. This is particularly true if the proteinuria cannot be reduced with therapy.

Spontaneous improvement in laboratory findings in those with isolated hematuria (without significant proteinuria or impairment of glomerular filtration rate [GFR]) has been reported. It appears to be more common in children and has been estimated to occur in between 5% and 30% of such cases.

There is a geographic variability in IgAN prognosis that is in large part explained by lead-time bias related to differing clinical thresholds for performing a kidney biopsy. Calculating the influence of other factors such as genetics, diet, ethnicity, or treatment is relevant but currently impossible to quantitate.