IgA nephropathy is the most prevalent primary chronic glomerular disease worldwide.
Typically manifests in childhood or young adult.
It is considered to be a slowly progressive disease among patients with out risk indicators, such as high-grade proteinuria, marked hypertension, and specific biopsy findings.
Estimated annual incidence of at least 2.5 persons for 100,000.
The incidence is likely to be underestimated.
Long-term studies report rates of kidney failure of up to 25% at 10 year follow up and up to 50% at 30 year follow up.
At least 30% of patients have progression to kidney failure within 20 to 30 years after diagnosis, despite standard care.
Pathogenesis involves 4 factors: Elevated levels of mucosal circulating galactose-deficient IgA1; their recognition by IgG or IgA-autoantibodies; pathogenic galactose-deficient IgA1autoantibody immune complexes form and are deposited in the mesangium; causing glomerular injury.
Diagnostic manifestation is the predominance of the IgA deposits either alone or with IgG, IgM, or both in the glomerular mesangium.
The frequency of IgA without IgG or IgM ranges from zero to more than 85%, depending on the center.
C3 and properdin are almost always found, while C4 or C 4d, mannose binding lectin and complement C5-9 are frequently noted while C1q is absent.
Alternative and lectin pathways of complement activation are possibly involved in the pathogenesis.
On light microscopy there is an increase in mesangial matrix and hypercellularity.
Light microscopy may also show focal necrosis, segmental scarring and crescents in Bowman’s space.
Electron microscopy shows immune deposits generally in the mesangial and paramesangial areas of the BM.
Has similar renal histologic features of Henoch-Shonlein purpura nephritis.
About 75% of children and young adults present with macroscopic hematuria during an upper respiratory or gastrointestinal tract illness.
Patients may have evidence of acute kidney injury.
Adult patients usually have proteinuria, microscopic hematuria, hypertension, alone or in combination.
In the United States more than 50% of all those older than 30 years of chronic kidney disease stage III-five.
Male to female ratio is 2:1 for children and adults.
In Asia the male: female ratio is 1:1.
The nephrotic syndrome is uncommon presentation.
Studies support the use of immunosuppressive therapy to target mesangial IgA deposits and circulating autoantibodies.
Involved in the pathogenesis of IgA nephropathy is the production of galactose -deficient IgA1.
The development of auto antibodies against galactose – deficient IgA1 leads to the formation of circulating immune complexes that deposit in the mesangium of the glomeruli which triggers an inflammatory response, complement activation and a dysregulated proliferative response and results and progressively worsening kidney damage.
A proliferation inducing ligand (APRIL) is implicated in the pathogenesis of IgG nephropathy.
IgA nephropathy appears to be the result of a multihit mechanism, starting with the production of IgA1 that is deficient in galactose residues in its hinge region, followed by the development of auto antibodies against galactose, deficient IgA1 and the subsequent formation of circulating immune complexes.
These immune complexes are deposited in the mesangial matrix leading to glomerular injury.
No disease specific therapy has been proven to prevent kidney failure
Guidelines recommend treatment with a blocker of the renin-angiotensin system in patients to have proteinuria with urinary protein excretion of more than one gram per day.
Treatment guidelines also suggest the use of systemic glucocorticoids in patients who have proteinuria of greater than one gram of urinary excretion per day in the GFR higher than 50 mL per minute despite supportive care.
Standard therapy with non-specific supportive measures blood pressure control, and treatment with angiotensin converting enzyme inhibitors or angiotensin receptor blockers for proteinuria have shown modest efficacy at best, to reduce the rate of progression of chronic kidney disease and end stage renal disease.
Non-specific immunosuppression with systemic or glucocorticoids has shown efficacy in high risk persons, but benefits generally wain without continued therapy.
In a randomized controlled trial of supportive care versus supportive care and immunosuppressive therapy over 3 years in patients with high-risk IgA nephropathy: there was no significant improvement in outcome but adverse effects were observed more frequently in those who received the immunosuppressive therapy with no change in the rate or decrease in the glomerular filtration rate (Rauen T et al).
Glucocorticoid therapy has been variably used, but its role remains controversial based on persistent uncertainty about its benefits and risks.
In a randomized clinical trial including 503 participates, a 6 to 9 month course of oral methylprednisolone in patients with IgA nephropathy and proteinuria greater than or equal to 1 g per day significantly reduced the risk of composite outcome of kidney function decline, kidney failure, or death due to kidney disease with an increased incidence of serious adverse events (TESTING Study Group).
In patients with IgA nephropathy, 12 months treatment with sibeprenlimab , a humanized monoclonal antibody that binds and neutralizes a proliferation inducing ligand (APRIL) significantly reduced proteinuria.