IgA nephropathy

IgA nephropathy is the most common primary chronic glomerular disease worldwide.

It commonly presents with macroscopic haematuria or asymptomatically with microscopic haematuria, proteinuria +/- hypertension picked up incidentally or during investigation for renal impairment. The condition remains a leading caused of chronic kidney disease and renal failure.

The diagnosis can be confirmed with a renal biopsy. There is no targeted therapy but angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor blockers (ARB) may be used for proteinuria and hypertension. In those with ongoing severe disease immunosuppressive therapies may be considered.

IgA nephropathy predominantly affects children and young adults.

Though the disease occurs at all ages, its incidence peaks in the second and third decade of life. In North American populations men are more commonly affected than women (2:1), whilst in Asia the ratio is close to even.

The condition is common in Asian populations, southern Europe and some Native American populations. It is relatively rare in those of African heritage.

Accurate estimates of prevalence and incidence are difficult to attain due to the large proportion of disease that is asymptomatic and the need for biopsy to formalise diagnosis. Changes consistent with IgA nephropathy are found on 20% of renal biopsies in Europe.

IgA1 nephropathy is characterised by an increased proportion of galactose deficient IgA.

IgA, or immunoglobulin A, is an antibody that exists as a dimer (i.e. two connected antibodies). There are two sub-types IgA1 (major subclass in serum) and IgA2 (major subclass in secretions).

It is thought that IgA nephropathy is a systemic condition that primarily causes pathology within the kidney. Galactose deficient IgA1 expose N-acetylgalactosamine in the hinge region of the antibody that is recognised by IgG and IgA1 leading to the generation of immune complexes.

These immune complexes deposit in the renal mesangium. This results in the release of various mediators that are toxic to the kidneys leading to renal impairment.

IgA nephropathy most commonly presents with macroscopic haematuria or asymptomatically with microscopic haematuria and proteinuria.

There are a number of characteristic patterns that patients may present with, which are discussed below. Overall the majority are asymptomatic, with slowly but progressive renal impairment. In all patients, around 25-30% develop renal failure within 20-25 years of presentation.

Macroscopic haematuria

Many children and young adults present with macroscopic haematuria, typically during an acute infective illness (upper respiratory tract or gastrointestinal). This presentation becomes increasingly uncommon with advancing age and is rare after 40.

A number of other features may accompany this presentation. Loin pain may be experienced secondary to stretching of the renal capsule and low grade fever may be experienced.

Microscopic haematuria

Older adults typically present this way with microscopic haematuria, modest proteinuria and hypertension. This may be picked up incidentally or during investigations for renal impairment. A significant proportion will have CKD at time of diagnosis.

Other

A relatively small proportion present with frank nephrotic syndrome (proteinuria, oedema and hypoalbuminaemia) or rapidly progressive glomerulonephritis (acute renal injury, haematuria and typical histological findings).

Renal biopsy is required to make a definitive diagnosis of IgA nephropathy.

The majority of the tests are non-diagnostic. Urine abnormalities are non-specific as are blood tests and imaging. Renal biopsy (when indicated) is diagnostic.

There are a number of advanced tests that look for immune complexes, galactose deficient IgA or microRNAs but none of these form part of routine care currently.

In addition to the investigations below, secondary causes should be excluded, including:

• IgA vasculitis
• IgA nephropathy secondary:
  • HIV
  • Inflammatory bowel disease
  • Cirrhosis
  • Other auto-immune disease
• IgA dominant infection related glomerulonephritis

Urine

Urinalysis: haematuria is characteristic, proteinuria is frequently present though rarely in the nephrotic range.

Urine microscopy: may demonstrate red cells and occasionally red cell casts.

Blood tests

• FBC
• Renal function
• LFTs
• Bone profile

Imaging

USS / CT KUB may be organised, typically to exclude other causes of given symptoms such as structural abnormalities.

Biopsy

Renal biopsy is required to make a definitive diagnosis of IgA nephropathy. It is an invasive procedure that is not without risk – primarily bleeding and infection. The decision to proceed to biopsy is made by nephrologists and is typically reserved for those with more severe disease.

Light, electron and immunofluorescence microscopy is performed on samples. Mesangial IgA deposits is characteristic. The Oxford MEST-C Classification is used to score biopsies. The full details are beyond the scope of this note, but in brief it scores 5 domains (MEST-C):

• Mesangial hypercellularity
• Endocapillary hypercellularity
• Segmental glomerulosclerosis
• Tubular atrophy/interstitial fibrosis
• Cellular or fibrocellular crescents

The primary focus of IgA nephropathy management is optimal supportive care, control of blood pressure and reduction of proteinuria.

Lifestyle modification

Advice aimed at optimising lifestyle and modifiable risk factors is key. Weight loss, exercise, smoking cessation and dietary changes should be supported where appropriate. Dietary sodium restriction in particular has been shown to improve outcomes.

ACE inhibitors/ARBs

Control of blood pressure and reducing proteinuria slows the progression of renal impairment and lowers cardiovascular risk.

ACE inhibitor or ARB are recommended for patients with hypertension or proteinuria > 0.5g/24h.

Further treatment options

In patients at high risk of progression (proteinuria > 0.5g/24h despite 90 days of optimal care) immunosuppressive therapy may be considered. The potential benefits and risks should be discussed. Consideration may be given to a course of corticosteroids for these patients. It should be avoided (or used with extreme caution) in patients at increased risk of complications:

• Obesity
• eGFR < 30
• Uncontrolled psychiatric illness
• Secondary disease (e.g. cirrhosis)
• Active peptic ulcer disease
• Diabetes
• Latent infections (e.g. TB)

In Chinese populations there is some evidence mycophenolate mofetil can be used as a steroid sparing agent. Tonsillectomy is not advised in Caucasian populations but is performed routinely in Japan on Japanese patients where improved outcomes have been demonstrated.

NOTE: Treatment of ‘variant’ forms of IgA nephropathy – e.g. IgA deposition with minimal change disease; IgA nephropathy with AKI or IgAN with rapidly progressive glomerulonephritis – is not covered here.

Around 25-30% of patients develop renal failure within 20-25 years of diagnosis.

The International IgAN Prediction Tool – which is calculated at the time of diagnosis can give an idea of the chance of progression to end-stage renal disease over a given period. 

Those with end-stage disease require renal replacement therapy with dialysis or renal transplant.