This is a form of glomerulonephritis that was first described by Berger and Hinglais in 1968.
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. Galactose deficiency of IgA molecules has been identified as being the most likely pathological mechanism.
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Oxford classification system
A new 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 renal 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 and 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)
Although not described until 1968, this is the most common form of acute glomerulonephritis. As it represents a spectrum of severity it is possible that the mildest cases are not diagnosed. It is more common in people of European or Asian ancestry than those of African descent. It is about twice as common in males as in 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.
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.
One study reported IgA nephropathy in three elderly patients with renal cell carcinoma.
The disease can be highly variable, ranging from microscopic haematuria to rapidly progressive glomerulonephritis. The majority of cases run a benign course.
- 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. The National Institute for Health and Clinical Excellence (NICE) has found that IgA nephropathy is the most common cause of isolated persistent microscopic haematuria.
- Of those that do not remit, there is a slow progression to end-stage renal failure (ESRF) in 1 to 2% per year.
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.
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 testing.
- 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.
- 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 (CRF) and end-stage renal failure (ESRF) 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. Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice with angiotensin receptor blockers (ARBs) in reserve. They protect renal function and may even be beneficial with normal blood pressure.
- A combination of an ACE inhibitor and the ARB losartan may lower urinary protein excretion compared with higher doses of ACE inhibitor monotherapy but patients need to be closely monitored for hyperkalaemia. Such a combination should be avoided in patients with advanced renal failure.
- Corticosteroids should be given for 6 months to patients with preserved renal 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 1, 3 and 5, with low-dose oral steroids every other day for 6 months. There may be benefit in extending beyond the 6-month period.
- Introduction of corticosteroids at an early stage in patients with proliferative IgA nephropathy slows the development of pathological histological changes and reduces proteinuria. In patients with modest proteinuria (1.5-3.5 g/day) corticosteroids slows deterioration of renal function.
- One study found that a combination of steroids with an ACE inhibitor was better than an ACE inhibitor alone in reducing the progression of renal disease.
- A combination of methylprednisolone and cyclophosphamide has been found to improve renal function and reduce haematuria and proteinuria in children with IgA nephropathy.
- One study has reported benefits with lisinopril in children with mild IgA nephropathy.
- The value of fish oil (omega-3 fatty acids) at a dose of 12 g a day is controversial with conflicting results but is frequently used in patients with declining renal function.
- 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.
- Protein restriction is of value in advanced renal impairment.
- Amongst other evidence-based interventions, it is suggested that if recurrent tonsillitis causes recurrent disease there is benefit from tonsillectomy.
- 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 donors, 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 (ESRF) occurs by 10 years in 15 to 20% and by 20 years in around 30%. 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 g 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.
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.
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.
Further reading & references
- IgA nephropathy, National Kidney Federation; (information for patients)
- Berger J, Hinglais N; Intercapillary deposits of IgA-IgG. J Urol Nephrol (Paris). 1968 Sep;74(9):694-5.
- Jean Berger; whonamedit.com
- Nicole Hinglais; whonamedit.com
- Narita I, Gejyo F; Pathogenetic significance of aberrant glycosylation of IgA1 in IgA nephropathy. Clin Exp Nephrol. 2008 Oct;12(5):332-8. Epub 2008 Apr 12.
- Cattran DC, Coppo R, Cook HT, et al; The Oxford classification of IgA nephropathy: rationale, clinicopathological Kidney Int. 2009 Sep;76(5):534-45. Epub 2009 Jul 1.
- Brake M; IgA Nephropathy, eMedicine, Mar 2010
- IgA Nephropathy, Online Mendelian Inheritance in Man (OMIM)
- Mimura I, Tojo A, Kinugasa S, et al; Renal cell carcinoma in association with IgA nephropathy in the elderly. Am J Med Sci. 2009 Nov;338(5):431-2.
- Feehally J; IgA nephropathy--a disorder of IgA production? QJM. 1997 Jun;90(6):387-90.
- Chronic kidney disease - not diabetic, Clinical Knowledge Summaries (July 2009)
- Abuelo JG, Esparza AR, Matarese RA, et al; Crescentic IgA nephropathy. Medicine (Baltimore). 1984 Nov;63(6):396-406.
- Roos A, van Kooten C; Underglycosylation of IgA in IgA nephropathy: more than a diagnostic marker? Kidney Int. 2007 Jun;71(11):1089-91.
- Barratt J, Feehally J; IgA nephropathy. J Am Soc Nephrol. 2005 Jul;16(7):2088-97. Epub 2005 Jun 1.
- Locatelli F, Pozzi C, Andrulli S; IgA nephritis: ACE inhibitors, steroids, both or neither? Nephrol Dial Transplant. 2006 Dec;21(12):3357-61. Epub 2006 Sep 15.
- Manno C, Torres DD, Rossini M, et al; Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with Nephrol Dial Transplant. 2009 Dec;24(12):3694-701. Epub 2009 Jul 23.
- Jiang XY, Mo Y, Sun LZ, et al; Efficacy of methylprednisolone, cyclophosphamide in pediatric IgA nephropathy Clin Nephrol. 2009 Jun;71(6):625-31.
- Nakanishi K, Iijima K, Ishikura K, et al; Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot Pediatr Nephrol. 2009 Apr;24(4):845-9. Epub 2008 Sep 30.
- Coppo R, Roccatello D, Amore A, et al; Effects of a gluten-free diet in primary IgA nephropathy. Clin Nephrol. 1990 Feb;33(2):72-86.
- Levey AS, Adler S, Caggiula AW, et al; Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis. 1996 May;27(5):652-63.
- Nolin L, Courteau M; Management of IgA nephropathy: evidence-based recommendations. Kidney Int Suppl. 1999 Jun;70:S56-62.
- Galla JH; IgA nephropathy. Kidney Int. 1995 Feb;47(2):377-87.
- Coppo R, D'Amico G; Coppo R, D'Amico G; Factors predicting progression of IgA nephropathies. J Nephrol. 2005 Sep-Oct;18(5):503-12.
- Shen PC, He LQ, Tang Y, et al; Clinicopathological characteristics and prognostic factors of asymptomatic IgA J Investig Med. 2010 Mar;58(3):560-5.
- Park YH, Choi JY, Chung HS, et al; Hematuria and proteinuria in a mass school urine screening test. Pediatr Nephrol. 2005 Aug;20(8):1126-30. Epub 2005 Jun 10.
|Original Author: Dr Laurence Knott||Current Version: Dr Laurence Knott|
|Last Checked: 21/06/2010||Document ID: 2307 Version: 22||© EMIS|
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