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.
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.
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 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).
IgAN is the most common primary glomerular disease with approximately 30% to 40% of patients progressing to end-stage kidney disease (ESKD) within 20 years.
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 IgAN, inherited as an autosomal dominant condition, has also been described.
One study reported IgAN 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.
Symptoms and findings
- 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 ESKD.
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 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 plama 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.
No specific therapy is available for IgAN. Lowering blood pressure and renin-angiotensin system inhibition remain the cornerstone of management. The use of steroids has been controversial but studies have shown a benefit of steroids in reducing proteinuria and reducing the risk of progression to CKD and ESKD.
- 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. ACE inhibitors are the drugs of choice with AIIRAs in reserve. They protect kidney function and may even be beneficial with normal blood pressure.
- However, more evidence is needed to understand the magnitude of benefit and the possible risks of anti-hypertensive or more specifically of ACE inhibitor/AIIRA therapy alone or in combination, and which specific types of patients with the IgAN might have the greatest potential for benefit.
- Combination therapy using ACE inhibitors and an AIIRA may provide more benefits to IgAN patients for reducing daily proteinuria.
- 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.
- Two-year combination therapy using prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the disease process ameliorates the activity of the acute phase of nephritis and improves the long-term outcome of severe childhood IgAN.
- One study found that a combination of steroids with an ACE inhibitor was better than an ACE inhibitor alone in reducing the progression of kidney disease.
- A combination of methylprednisolone and cyclophosphamide has been found to improve kidney function and reduce haematuria and proteinuria in children with IgAN.
- One study has reported benefits with lisinopril in children with mild IgAN.
ESKD requires dialysis or transplantation. Recurrence of IgAN after kidney transplantation is an important cause of graft failure. Tonsillectomy improves not only clinical findings but also ameliorates histological damage caused by recurrent IgAN after kidney transplantation.
In the majority this is a benign disease but CKD and ESKD may eventually appear in 30-40% of patients. 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.
The degree of proteinuria is one of the strongest predictors of outcome. The risk for CKD increases with higher levels of proteinuria.
Other features of poor prognosis are sustained hypertension, impaired kidney function, and persistent haematuria. 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.[20, 21]
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.
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