IgA Nephropathy (Berger's Disease)

This is a form of glomerulonephritis that was first described by Berger and Hinglais in 1968.^1,2,3 It should not be confused with Buerger's disease that is thrombo-angiitis obliterans, a rare vascular disease of smokers. Buerger, being an Austrian name is pronounced Bur-ger whilst Berger, being French, is pronounced Bur-shay.

Berger's disease is often the name attached to the mildest form of this IgA nephropathy. It is caused by immune complexes of IgA that become lodged in the glomeruli followed by complement fixation. This is unusual because IgA tends to be associated with immunity on mucosal surfaces and normally IgA is unable to activate complement. The alternative complement fixation pathway is apparently used. Pathology shows a spectrum of glomerular lesions, but mesangial proliferation with prominent IgA deposition is present in most biopsies.

Although not described until 1968, this is the commonest form of acute glomerulonephritis. As it represents a spectrum of severity it is possible that the mildest cases are not diagnosed. It is commoner in people of European or Asian ancestry than those of African descent. It is about twice as common in males as females. Of biopsies performed for glomerular disease, IgA nephropathy is found in about 40% in Asia, 20% in Europe and 10% in North America. Prevalence is high in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, but low in the United Kingdom, Canada, and the United States.
It is uncommon below the age of 10 and 80% of cases are diagnosed between the ages of 16 and 35.

Risk factors⁴

It is associated with a number of other diseases including Henoch-Schönlein purpura. IgA deposits are also found in systemic lupus erythematosis, hepatitis, dermatitis herpetiformis, and ankylosing spondylitis. They 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 has also been described.⁵

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

Symptoms and findings^4,6

• In 40 to 50% of patients there is gross haematuria, usually with an upper respiratory tract infection or, less often, gastroenteritis.
• In 30 to 40% of patients there are no symptoms but urine shows erythrocytes, casts and proteinuria.
• Much less often the presentation may be in acute renal failure that usually reverses spontaneously or chronic renal failure.
• In around 80% of patients there is an upper respiratory tract infection and either at the onset or within the first 24 to 48 hours there is gross haematuria that lasts for less than 3 days. The urine is red or brown and in a third of patients there is loin pain, presumably due to swelling of the renal capsule.
• Gross haematuria is not usually accompanied by clots. It 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 failure in 1 to 2% per year.

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 findings⁷

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.

• 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 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 renal function with urea and electrolytes, creatinine and a 24 hours creatinine clearance test.
• Plasma levels of IgA are raised in about half of cases but it 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.⁸
• The current gold standard diagnostic test of IgA nephropathy is by renal biopsy. Light microscopy, electron microscopy and immunofluoresence are required.

• In the majority this is a benign disease but chronic renal failure and end-stage renal failure may eventually appear in 20 to 40% of patients. This is a significant number with a serious adverse outcome and a benign course is usually a retrospective diagnosis. There is no cure but treatment can delay the need for dialysis or transplantation.
• Patients with haematuria but no albuminuria need monitoring by urinalysis, renal function and checking blood pressure.
• Hypertension needs early and aggressive treatment. ACE inhibitors are the drugs of choice with angiotensin receptor blockers in reserve. They protect renal function and may even be beneficial with normal blood pressure. A combination of the 2 drugs may offer further benefit.¹⁰
• The role of immunosuppressive therapy in IgA nephropathy remains controversial.¹¹ The challenge is to identify those in whom the condition is likely to progress. The consensus appears to be is that isolated microscopic haematuria with little or no proteinuria does not warrant treatment whereas proteinuria greater than 1g/24hours does. Early treatment with prednisone and azathioprine appears to be beneficial in preventing deterioration.¹¹ Rapidly progressive glomerulonephritis should be treated (usually with intravenous prednisolone followed by pulsed oral prednisolone and cyclophosphamide). This does seem to slow progression.
• The value of fish oil (omega-3 fatty acids) at a dose of 12 grams a day is controversial with conflicting results. A meta-analysis suggested that the trial was under-powered, should have run longer than two years, and the treatment has not been supported by subsequent data.¹²
• Dietary restriction of gluten, meat and diary produce has been suggestive but its value is unproven. If gluten sensitivity is demonstrated it must be excluded.¹³
• Protein restriction is of value in advanced renal impairment.¹⁴
• Amongst other evidence-based interventions, it is suggested that if recurrent tonsillitis causes recurrent disease there is benefit from tonsillectomy.¹⁵
• End-stage renal failure requires dialysis or transplantation. IgA complexes may form again in the transplanted kidney and this occurs with variation from 20 to 60%. The rate is higher in transplants from live related doors, suggesting a possible genetic vulnerability. However, the disease continues to progress slowly with loss of graft function in only 10%.

In the majority the disease is benign but end stage renal failure occurs by 10 years in 15 to 20% and by 20 years in around 30%.¹⁶ These figures are based on those who have had renal biopsies and so those with milder disease presumably do better than this. Those with microscopic haematuria seem to fare worse than those with macroscopic disease. This could be because they present later.

Other features of poor prognosis are sustained hypertension, impaired renal function, persistent haematuria, and proteinuria in excess of 1 gram a day. Histological findings of interstitial fibrosis, tubular atrophy, and glomerular scarring give a worse outcome. As with other glomerular diseases, the risk of progression is more closely correlated with tubulointerstitial pathology than with glomerular disease.¹⁷

Pregnancy is usually uneventful unless there is poorly controlled blood pressure, a bad histological picture or poor renal function with a creatinine clearance of less than 70 ml a minute. ACE inhibitors and angiotensin II receptor antagonists must be stopped before trying to conceive as they are markedly teratogenic.⁴

The value of a screening programme to detect microscopic haematuria in school children in Korea has been demonstrated but its benefits in the UK with a much lower prevalence may be doubted.¹⁸