IgA nephropathy

Since its first description by Berger and Hinglais in 1968, IgA nephropathy (IgAN) has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease (CKD) in developed countries.¹

What is IgA nephropathy?

IgAN is an autoimmune renal disease arising from consequences of increased circulating levels of IgA1 with galactose-deficient hinge-region O-glycans. For this to cause kidney injury, several further processes are required, including synthesis of circulating antibodies directed against the aberrantly glycosylated O-linked hinge-region glycans to form immune complexes, accumulation of the complexes in the mesangium, and activation of mesangial cells. Genetic factors apparently influence the expression of these processes.²

Oxford classification system³

An updated classification system has been developed by an international consensus working group, based on specific pathological features. Four variables detected on renal biopsy have been found to be independent prognostic factors for progression to kidney disease. These are:

• The mesangial hypercellularity score (an estimate of the density of the mesangial cells around renal blood vessels).

• Segmental glomerulosclerosis (a reflection of scar tissue developing in glomeruli).

• Endocapillary hypercellularity (an increase in the number of cells within the glomerular capillary lumina).

• Tubular atrophy/interstitial fibrosis (interstitial fibrosis reflects an increase in supporting connective tissue in the renal parenchyma; tubular atrophy implies the presence of tubules with thick redundant basement membranes or a reduction in tubular diameter).

How common is IgA nephropathy? (Epidemiology)^{1 4}

IgA nephropathy is the most common primary glomerular disease. It has a worldwide incidence of 2.5 per 100,000 with higher prevalence noted in Eastern and Pacific Asian countries. It is rare in African countries. In European and American patients there is a 2:1 male: female ratio.

Diagnosis peaks during the second and third decades.

Associated diseases

It is associated with a number of other diseases, including Henoch-Schönlein purpura. IgA deposits are also found in systemic lupus erythematosis (SLE), hepatitis, dermatitis herpetiformis and ankylosing spondylitis. It may also be associated with cirrhosis and coeliac disease and it has occasionally been linked to HIV infection.

A familial form of IgA nephropathy, inherited as an autosomal dominant condition, has also been described.⁵

Presentation⁶

The disease can be highly variable, ranging from microscopic haematuria to rapidly progressive glomerulonephritis. The majority of cases run a benign course.

Symptoms and findings⁴

• May present with gross haematuria, usually with an upper respiratory tract infection or, less often, gastroenteritis.

• Alternatively, there may be no symptoms but urine shows erythrocytes, casts and proteinuria.

• Much less often the presentation may be in acute kidney injury that usually reverses spontaneously, or CKD.

• Most patients have a history of an upper respiratory tract infection and, either at the onset or within the first 24-48 hours, there is gross haematuria that lasts for less than three days. The urine is red or brown and there may also be loin pain.

• Gross haematuria tends to occur in the younger patients whilst microscopic haematuria tends to occur with the older age range.

• Illnesses that can precipitate haematuria include urinary tract infection, pneumonia, staphylococcal infection, acute gastroenteritis, influenza and glandular fever.

• Between episodes of macroscopic haematuria there may be persistent microscopic haematuria.

• Of those that do not remit, there is a slow progression to end stage renal disease (ESRD).

Signs

Usually there is no abnormality to find, although occasionally there may be hypertension. This is uncommon at presentation but may occur if renal function fails. If glomerulonephritis leads to nephrotic syndrome there will be oedema.

Other findings

Microscopic haematuria is usually accompanied by a light albuminuria. Heavy proteinuria to cause hypoalbuminaemia and oedema is an uncommon presentation that occurs in about 5%. It may remit or persist.

Investigations⁶

• Urine testing by dipstick will probably show light-to-moderate albumin and blood.

• Urine microscopy is required for red blood cells, leukocytes and casts.

• Measurement of 24 hours of protein excretion should be undertaken. A semi-quantitative estimate from a spot urine and extrapolation based on creatinine content is less satisfactory. If the patient is over 50, protein electrophoresis should be undertaken to exclude myeloma.

• Assess kidney function with U&Es, creatinine and a 24-hour creatinine clearance test.

• Plasma levels of IgA are raised in about half of cases. Raised levels of plasma IgA also occurs in other conditions and the predictive value of this test is poor.

• Serum undergalactosylated IgA is being investigated as a diagnostic test and may lead to further elucidation of the pathogenesis of the condition.

• The current gold-standard diagnostic test of IgAN is by renal biopsy. Light microscopy, electron microscopy and immunofluoresence are required.

Management of IgA nephropathy^{7 8}

No specific therapy is available for IgAN so the aim is supportive management. Lowering blood pressure and renin-angiotensin system inhibition remain the cornerstone of management. Patients should be advised to follow a low-salt diet.

• Patients with haematuria but no albuminuria need monitoring by urinalysis, kidney function and checking blood pressure.

• Angiotensin-converting enzyme (ACE) inhibitors/angiotensin-II receptor antagonists (AIIRAs):
  

  • Hypertension needs early and aggressive treatment, titrating up to maximum tolerated dose. ACE inhibitors or AIIRAs are the drugs of choice . They protect kidney function and are also beneficial when blood pressure is normal.

• Steroids:⁹
  

  • Steroid therapy is associated with a decrease of proteinuria and with a statistically significant reduction of the risk of ESKD.

  • Corticosteroids should be given for six months to patients with preserved kidney function, nephrotic syndrome and few histological changes on light microscopy. A typical regime is 1 g of intravenous methylprednisolone for three consecutive days at the beginning of months one, three and five, with low-dose oral steroids every other day for six months. There may be benefit in extending beyond the six-month period.

  • Introduction of corticosteroids at an early stage in patients with proliferative IgAN slows the development of pathological histological changes and reduces proteinuria. In patients with modest proteinuria (1.5-3.5 g/day) corticosteroids slow deterioration of kidney function.

  • Immunosuppressants (mycophenolate, azathioprine, cyclophosphamide) are reserved for patients at high risk of progression, with progressive crescentic IgA nephropathy and are to be avoided if the biopsy shows advanced interstitial fibrosis or tubular atrophy.¹

ESRD requires dialysis or transplantation. Recurrence of IgAN after kidney transplantation is an important cause of graft failure.¹¹

There is evidence that tonsillectomy slows down the progression of IgA nephropathy.¹² However, it is not currently recommended in guidelines, unless otherwise indicated due to recurrent infection.⁸ .

Prognosis

In the majority this is a benign disease but CKD and ESRD may eventually appear in 40% of patients within 20 years.^{1 4} This is a significant number with a serious adverse outcome, and a benign course is usually a retrospective diagnosis.

Mortality in patients with IgAN was found in one study to be twice the expected rate, but not significantly increased before renal replacement therapy.¹³

The degree of proteinuria and hypertension and presence of reduced eGFR at time of biopsy are the strongest predictors of poor outcome.¹ The risk for CKD increases with higher levels of proteinuria. Histological features associated with a poor prognosis include segmental glomerulosclerosis, interstitial fibrosis, and endocapillary proliferation.