IgA Nephropathy

• 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.

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

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.

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

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.

• Selvaskandan, H., Dillon, M. & Barratt, J. IgA Nephropathy: driving innovation with a rare renal disease registry, J. Kidney Care. 2017 Jul; pp 205–211. https://doi.org/10.12968/jokc.2017.2.4.205
• Wyatt RJ, Julian BA. IgA Nephropathy. N Engl J Med. 2013 Jun 20;368(25):2402-14. doi: 10.1056/NEJMra1206793.
• Lai KN, Tang SC, Schena FP, Novak J, Tomino Y, Fogo AB, Glassock RJ. IgA Nephropathy. Nat Rev Dis Primers. 2016 Feb 11;2:16001. doi: 10.1038/nrdp.2016.1.
• Feehally J, Barratt J. The Genetics of IgA Nephropathy – an Overview from Western Countries. Kidney Dis 2015;1:33-41. doi:10.1159/000381738.
• Yeo SC, Liew A, Barratt J. Emerging Therapies in IgA Nephropathy. Nephrology (Carlton). 2015 Jun 1. doi: 10.1111/nep.12527