IgA Nephropathy – Clinician Information

Immunoglobulin A nephropathy (IgAN) is the commonest pattern of glomerulonephritis seen in the Western world. It is an important cause of progressive kidney disease with 25-30% of patients developing ESRD within 25 years of diagnosis.

IgAN is defined by the predominant deposition of polymeric IgA1 in the glomerular mesangium.

  • Epidemiology
    • There is a male predominance in Western countries which is not seen in Asia.
    • Peak incidence in 2nd and 3rd decades.
    • There is wide geographic variation in incidence, with the highest incidence reported in the Pacific rim (this may reflect differing approaches to renal biopsy for minor urine abnormalities).
    • Prevalence of subclinical (asymptomatic and undiagnosed) IgAN may be as high as 16% of general population.
  • Aetiology

    <10% of cases have familial IgA nephropathy.

    • Genome-wide linkage analysis has demonstrated linkage of IgAN to 6q22-23 and the putative gene locus IGAN1
    • There are no obvious candidate genes within the linked interval
    • It is not certain that genetic findings from these families will have direct bearing on more typical sporadic cases of IgAN

    >90% of cases are sporadic and aetiology is unknown.

    • No evidence for involvement of a specific infectious agent despite association of macroscopic haematuria with mucosal inflammation
    • No evidence for hypersensitivity to food antigens in the majority of cases with exception of small group of patients with coeliac disease
    • Abnormal O-glycosylation of IgA1 hinge region thought to promote formation of circulating IgA immune complexes with propensity for mesangial deposition and mesangial cell activation
  • Natural History

    The perceived overall cohort risk is heavily influenced by different diagnostic approaches.

    Centres with a low threshold for renal biopsy for patients with mild urine abnormality, particularly those working in countries where urine screening programs are established, will likely diagnose IgAN in a larger number of patients with mild disease and good prognosis, thus favourably influencing the overall outcome of the cohort.

    It is generally accepted that:

    • <10% have complete resolution of urinary abnormalities
    • Episodes of macroscopic haematuria become less frequent with time after diagnosis, although majority of patients will have persistent microscopic haematuria
    • 5% will reach ESRD per year
    • 25-30% will require renal replacement therapy within 20-25 years

    Recurrence after renal transplantation:

    • This is assuming increasing importance as a cause of graft failure as control of rejection improves
    • It is typically slowly progressive although occasional patients will have a rapidly progressive course
    • At 5 years a 5% risk of graft failure due to recurrence, a 13% risk of significant graft dysfunction, and a risk of IgA deposition of at least 50%.
    • The risk of graft loss increases to 25% if first graft was lost to recurrence
    • There is no consistent evidence that these risks differ between living and cadaveric donors
    • There is no evidence that immunosuppressive regimen alters incidence of IgAN recurrence or the prognosis of recurrence in the short term
  • Clinical Features

    Symptoms

    • 30-40% of patients present with macroscopic haematuria 12-72 hours after development of a mucosal infection (most commonly upper respiratory tract)
    • 30-40% patients are asymptomatic and are identified following incidental urine testing with microscopic haematuria and/or proteinuria
    • 5% patients develop nephrotic syndrome
    • <5% patients present with AKI.
    • <5% patients present with malignant hypertension
    • Remaining patients are identified following investigation of hypertension, usually associated with microscopic haematuria and or proteinuria

    Signs

    • There are no specific physical signs diagnostic of IgAN
    • Occasionally patients may exhibit loin pain (unilateral or bilateral), the relationship of loin pain to active glomerulonephritis is ill-understood

    Differential Diagnosis

    The diagnosis of IgAN requires a renal biopsy.

    Primary IgAN must be distinguished from other secondary forms of IgAN associated with:

    • Chronic liver disease, particularly alcoholic cirrhosis (thought to be due to impaired IgA immune complex clearance by the liver)
    • HIV and AIDS (associated with high serum IgA level)
    • Coeliac disease (in a small proportion of patients adherence to a gluten free diet can lead to reduced proteinuria and improvement of renal function
    • Henoch Schönlein Purpura (a small vessel vasculitis with renal biopsy appearances indistinguishable from IgA nephropathy)
    • Mesangial deposition of IgA, along with other immunoglobulin classes and complement may also be a feature of lupus nephritis but the clinical and serologic features usually present no diagnostic difficulty
    • There have also been a number of reports of an IgA-dominant postinfectious glomerulonephritis associated with methicillin sensitive and resistant Staphylococcus aureus infection. This disease is marked by severe glomerular changes on renal biopsy, nephrotic range proteinuria and rapid decline in renal function with many patients developing irreversible ESRD.
  • Investigations

    General Investigations

    • Assessment of renal function, urinary protein leak and renal size are mandatory for the investigation of suspected glomerulonephritis.
    • Raised serum IgA1 levels are found in 30–50% of all patients, but are less common in children and do not correlate with disease activity or severity.
    • A high proportion of λ light chain, rather than the normal predominance of the κ isotype, is also a distinctive feature of serum IgA in IgAN although the significance of this is unknown.
    • Complement components C3 and C4, and CH50 in the serum are usually normal but there is some evidence of systemic complement activation with more specific testing.
    • Circulating autoantibodies, IgA-rheumatoid factors and IgA containing immune complexes have been reported in IgAN but none appear to be disease specific.
    • Laboratory checks for liver function and hepatitis B status are sufficient to exclude the common causes of secondary IgAN.

    Special Investigations

    • The diagnosis of IgAN requires a renal biopsy.
    • No accumulation of clinical and laboratory evidence has sufficient specificity and sensitivity to avoid the need for diagnostic biopsy.
    • There has been a single report suggesting measurement of IgA1 O-glycosylation may in the future be used to diagnose IgAN but this remains speculative at present.

    Renal Biopsy Features

    • Mesangial IgA deposits are the defining hallmark of IgAN and can be identified by immunofluorescence or immunoperoxidase techniques.
    • IgA deposits are diffuse and global even if light microscopic changes are focal and segmental.
    • Heavy mesangial IgA deposition may be seen with no light microscopic change.

    Light Microscopy

    • Light microscopic abnormalities may be minimal, but the commonest appearance is mesangial hypercellularity which is usually diffuse and global.
    • Progressive disease is associated with relentless accumulation of mesangial matrix.
    • Crescentic change may be superimposed on diffuse mesangial proliferative glomerulonephritis with or without associated segmental necrosis.
    • Crescents are common in biopsies performed during episodes of macroscopic haematuria with renal impairment.
    • Tubulointerstitial changes do not differ from those seen in other forms of progressive glomerulonephritis.

    Immunohistology

    • IgA sole immunoglobulin in 15% biopsies.
    • IgG present in 50-70% and IgM in 31-66% of biopsies although staining usually less intense than IgA.
    • Co-deposition of IgG and IgM unrelated to the extent of glomerular injury or clinical outcome.
    • C3 deposition is usual and has the same distribution as IgA. The pathological significance
    • IgA deposits may extend beyond the mesangium to the periphery of the glomerular capillaries and this has been associated with a worse prognosis.

    Electron Microscopy

    • Mesangial and paramesangial electron dense deposits are the ultrastructural manifestation of mesangial IgA deposition.
    • Capillary loop deposits are usually subendothelial but can be intramembranous or subepithelial and are associated with worse clinical outcome in adults.
    • The quantity, size, shape and density of deposits vary from glomerulus to glomerulus and from one mesangial zone to another.
    • Glomerular basement membrane shows localised abnormalities in 15-40% cases. GBM abnormalities are associated with heavy proteinuria, more severe glomerular changes and crescent formation.
    • A proportion of patients have diffuse uniform global thinning of the GBM indistinguishable from thin membrane nephropathy. It is not clear whether this group of patients have any defining clinical or prognostic characteristics compared to most IgAN.

    A number of classifications of IgAN based on light microscopic findings have been proposed (for example those of Lee and Haas), but there is little agreement about their relative utility. The International IgA Nephropathy Network with the Renal Pathology Society have developed the Oxford Classification MEST score which has now been validated in North American, European and Asian cohorts and is now widely accepted as the scoring system of choice in IgAN.

  • Risk Stratification

    Many studies have identified features at presentation which mark a poor prognosis.

    Although prognostic formulae using simple clinical and laboratory data have been proposed there is not yet sufficient consensus to recommend they are used in clinical practice for the prediction of individual progression risk.

  • Treatment

    General Measures

    As with all causes of CKD, patients with IgAN and CKD3, 4 & 5 must pay close attention to cardiovascular risk and:

    • stop smoking
    • eat a healthy & balanced diet
    • take regular exercise

    Recurrent Macroscopic Haematuria

    • No specific treatment required.
    • No role for prophylactic antibiotics.
    • No role for tonsillectomy.

    Microscopic Haematuria and <1 g/24h Proteinuria

    • No specific treatment required.
    • Consider ACEI and/or ARB.

    Nephrotic Syndrome

    • Only treat with corticosteroids if there are histological features of minimal change disease.
    • Generic management of nephrotic syndrome.

    Acute Kidney Injury

    • A renal biopsy is almost always required.
    • Acute tubular necrosis: provide supportive care
    • Crescentic IgAN: If there is active glomerular inflammation, deteriorating renal function and no significant chronic damage then treat with cyclo-phosphamide and corticosteroids (as for small vessel vasculitis). Otherwise provide supportive management

    Slowly Progressive IgAN

    • Blood pressure control: aim for <127/75 mmHg, greatest benefit with maximal renin angiotensin system blockade.
    • Proteinuria >1g/24 h: aim for maximal renin angiotensin system blockade.
    • There is no conclusive evidence for:
      • corticosteroids
      • mycophenolate mofetil
      • cyclophosphamide
      • fish oil
      • anticoagulation or antiplatelet agents
    • A number of high quality clinical trials are now recruiting in IgAN testing novel immunomodulatory agents- see clinicaltrials.gov for further information
  • Follow Up

    Patients with CKD 1-3 can be followed up in primary care.

    Patients with progressive renal decline and CKD 4 and 5 require continued nephrological review on a 2-6 monthly basis dependent upon their eGFR.

  • Pregnancy

    As with other chronic glomerulonephritides pregnancy-related complications in IgAN are increased when there is:

    • Renal impairment (Cr >150 μmol/l)
    • Proteinuria (>1g / 24h)
    • Hypertension (either on treatment or >140/90)

    Patients with high-risk clinical profiles should be offered preconception counselling and when pregnant careful monitoring in a combined renal-obstetric clinic.

  • Prognosis

    25-30% of patients will require renal replacement therapy within 20-25 years.

    Those at greatest risk of progressive renal failure are patients with significant proteinuria, hypertension and impaired renal function at the time of renal biopsy

  • Further Reading
IgA Nephropathy Clinician Information Version 1 Updated September 2016
Written by the IgA Nephropathy Rare Disease Group