Residency · Residency · Nephrology

IgA Nephropathy and IgA Vasculitis

Introduction

IgA nephropathy, also known as Berger disease, is the most common primary glomerulonephritis worldwide, though its prevalence varies substantially by geographic region. In East Asia, IgA nephropathy accounts for 40 to 50 percent of glomerular disease on biopsy, compared to 20 to 30 percent in Europe and 10 to 15 percent in North America. IgA vasculitis, formerly known as Henoch-Schonlein purpura, is a systemic small-vessel vasculitis characterized by IgA-dominant immune deposits, and renal involvement in IgA vasculitis is histologically identical to IgA nephropathy. Despite being the most common glomerulonephritis, IgA nephropathy carries a significant long-term risk, with 15 to 40 percent of patients progressing to end-stage renal disease over 20 to 30 years.

Pathogenesis: Multi-Hit Hypothesis

Hit 1: Galactose-Deficient IgA1 (Gd-IgA1)

The pathogenesis of IgA nephropathy is understood through a multi-hit model, with each successive hit required for disease manifestation. The first hit involves the production of galactose-deficient IgA1. The IgA1 molecule has a hinge region containing O-linked glycans that normally bear galactose residues. In IgA nephropathy, these glycans are deficient in galactose, exposing underlying N-acetylgalactosamine residues. This aberrantly glycosylated IgA1 is produced primarily by mucosal plasma cells in the tonsils and intestinal gut-associated lymphoid tissue. Genetic susceptibility plays a significant role, with genome-wide association studies identifying more than 20 risk loci, including C1GALT1, which encodes the galactosyltransferase responsible for IgA1 glycosylation. Serum levels of galactose-deficient IgA1 are elevated in patients with IgA nephropathy and in some first-degree relatives, though elevated levels alone are insufficient to cause disease.

Hit 2: Autoantibody Formation

The second hit is the generation of anti-glycan autoantibodies, either IgG or IgA, that recognize the aberrant hinge region glycans on galactose-deficient IgA1. These autoantibodies form circulating immune complexes with the galactose-deficient IgA1, and their levels correlate with disease severity and risk of progression.

Hit 3: Immune Complex Deposition

The third hit is the deposition of the circulating immune complexes in the glomerular mesangium. Once deposited, mesangial IgA activates complement through the alternative and lectin pathways, with C3 and mannose-binding lectin deposition commonly observed on biopsy. The activated mesangial cells proliferate, release pro-inflammatory cytokines including interleukin-6 and TGF-beta, and increase extracellular matrix production.

Hit 4: Glomerular Injury

The fourth hit encompasses the downstream glomerular injury resulting from the immune-mediated mesangial activation. This includes mesangial expansion, endocapillary proliferation, crescent formation in severe cases, podocyte injury leading to proteinuria, and tubulointerstitial inflammation and fibrosis that drive progressive CKD.

<image>Four-panel illustration of the multi-hit pathogenesis of IgA nephropathy. Panel 1: Show a mucosal plasma cell producing IgA1 with galactose-deficient O-glycans on the hinge region, comparing normal IgA1 glycosylation (galactose and sialic acid present) versus Gd-IgA1 (exposed N-acetylgalactosamine). Panel 2: Show circulating autoantibodies (IgG and IgA) binding to the exposed glycan epitopes on Gd-IgA1, forming immune complexes. Panel 3: Show the immune complexes depositing in the glomerular mesangium, with mesangial cell activation and complement activation (alternative and lectin pathways). Panel 4: Show the downstream glomerular injury: mesangial proliferation, matrix expansion, podocyte foot process effacement, crescent formation, and tubulointerstitial fibrosis.</image>

Clinical Presentation

IgA Nephropathy

The most classic presentation of IgA nephropathy is synpharyngitic gross hematuria, in which painless macroscopic hematuria develops within 1 to 2 days of an upper respiratory infection. This temporal relationship is a critical distinguishing feature from post-infectious glomerulonephritis, which has a latency period of 1 to 3 weeks between the inciting infection and the onset of nephritis. However, the most common presentation in adults is persistent microscopic hematuria with or without proteinuria, often discovered incidentally during routine evaluation. Approximately 5 percent of patients present with full nephrotic syndrome, reflecting extensive podocyte injury. Crescentic IgA nephropathy, though uncommon, is an aggressive variant presenting as rapidly progressive glomerulonephritis with AKI and active sediment. Many patients present with already established CKD from insidious proteinuric disease. IgA nephropathy has a peak incidence in the second and third decades of life with a male predominance of approximately 2:1.

IgA Vasculitis (Henoch-Schonlein Purpura)

IgA vasculitis is predominantly a pediatric disease with peak incidence between 3 and 10 years of age, though it can occur in adults, in whom renal involvement tends to be more severe. The classic clinical tetrad consists of palpable purpura that is non-thrombocytopenic, arthralgia or arthritis, abdominal pain from gastrointestinal vasculitis with the risk of intussusception, and renal involvement that is histologically identical to IgA nephropathy on biopsy. Renal involvement occurs in 30 to 50 percent of affected children and up to 80 percent of adults, and adult IgA vasculitis carries a higher risk of progressing to CKD and ESRD than the pediatric form.

Diagnosis

Renal Biopsy (Definitive)

The definitive diagnosis of IgA nephropathy requires renal biopsy. Light microscopy reveals mesangial hypercellularity and matrix expansion as the most characteristic findings, with endocapillary proliferation in more severe cases, segmental sclerosis in chronic disease, and crescents in crescentic IgA nephropathy. Immunofluorescence demonstrates dominant or co-dominant mesangial IgA deposition, which is the sine qua non for the diagnosis, frequently accompanied by C3 and with IgG and IgM that may be present but are subordinate to IgA. The absence of C1q is notable, as its presence should raise suspicion for lupus nephritis rather than primary IgA nephropathy. Electron microscopy reveals electron-dense mesangial deposits, with paramesangial, subendothelial, and subepithelial deposits in more severe disease.

Oxford Classification (MEST-C)

The Oxford classification, developed through the International IgA Nephropathy Network, standardizes the pathologic scoring of IgA nephropathy and provides prognostic information. The M score reflects mesangial hypercellularity, scored as M0 when fewer than 50 percent of glomeruli are affected and M1 when 50 percent or more are involved. The E score reflects endocapillary hypercellularity, scored as E0 when absent and E1 when present. The S score reflects segmental sclerosis, scored as S0 when absent and S1 when present. The T score reflects tubular atrophy and interstitial fibrosis, graded as T0 for 0 to 25 percent of the cortical area, T1 for 26 to 50 percent, and T2 for more than 50 percent. The C score, added in the 2016 update, reflects crescents, graded as C0 for absent, C1 for crescents in fewer than 25 percent of glomeruli, and C2 for 25 percent or more. The T score is the strongest independent predictor of renal outcome, as tubular atrophy and interstitial fibrosis represent irreversible structural damage. The E and C scores are potentially modifiable with immunosuppressive therapy.

Serologic Findings

Serum IgA levels are elevated in approximately 50 percent of patients but are neither sensitive nor specific for the diagnosis. Complement levels, including C3 and C4, are typically normal. Serum galactose-deficient IgA1 is a research biomarker that is not yet routinely available in clinical practice. ANCA, anti-GBM, and ANA are characteristically negative.

Prognosis and Risk Stratification

Clinical Predictors of Progression

Proteinuria exceeding 1 gram per day is the strongest clinical predictor of disease progression, and sustained proteinuria despite RAAS blockade indicates a particularly poor prognosis. Additional risk factors include hypertension, reduced eGFR at the time of presentation, persistent microscopic hematuria, male sex, and older age at diagnosis.

International IgAN Prediction Tool

A validated prediction model incorporating race and ethnicity, age, eGFR, mean arterial pressure, proteinuria, MEST scores, and immunosuppression use estimates the 5-year risk of 50 percent eGFR decline or ESRD and is available online for clinical use.

Management

Supportive Care (All Patients)

Optimized supportive care forms the foundation of IgA nephropathy management for all patients. RAAS blockade with an ACE inhibitor or ARB should be titrated to the maximum tolerated dose, with a target proteinuria below 1 gram per day and ideally below 0.5 grams per day. Blood pressure should be controlled to a target below 130/80 mmHg, with a lower target of 125/75 if proteinuria exceeds 1 gram per day. SGLT2 inhibitors are now recommended as part of standard supportive care for proteinuric IgA nephropathy with an eGFR of 20 or above, based on the subgroup analyses of the DAPA-CKD and EMPA-KIDNEY trials demonstrating benefit in this population. Dietary sodium restriction to less than 2 grams per day enhances the efficacy of RAAS blockade. Fish oil supplementation, with omega-3 fatty acids at 4 grams per day, has shown modest benefit in some studies and is suggested as a consideration by KDIGO, though the evidence remains limited.

Immunosuppressive Therapy

Corticosteroids

The TESTING trial, published in 2022, demonstrated that a reduced-dose methylprednisolone protocol starting at 0.4 mg/kg/day with a maximum of 32 mg and tapered over 6 months significantly reduced the risk of 50 percent eGFR decline or ESRD with a hazard ratio of 0.53. Notably, the original full-dose protocol was stopped early due to serious adverse events, primarily infections, highlighting the importance of using the reduced-dose regimen. The STOP-IgAN trial in 2015 showed that immunosuppression with steroids alone or in combination with cyclophosphamide and azathioprine reduced proteinuria but did not improve long-term renal outcomes and increased infection risk. The current approach reserves corticosteroids for patients with persistent proteinuria exceeding 0.75 to 1 gram per day despite at least 90 days of optimized supportive care including maximal RAAS blockade and an SGLT2 inhibitor.

Targeted Complement Therapy

Complement-directed therapies represent a promising frontier in IgA nephropathy treatment. Narsoplimab, a MASP-2 inhibitor targeting the lectin pathway, showed initial promise but did not receive FDA approval. Iptacopan, a factor B inhibitor of the alternative pathway, is in ongoing phase III trials. Cemdisiran, a complement C5 siRNA, is in early-phase development.

Targeted B-Cell Therapy

The NEFIGAN trial demonstrated that targeted-release budesonide (Nefecon/Tarpeyo) at 16 mg per day for 9 months reduces proteinuria by 30 to 50 percent by acting locally on gut-associated lymphoid tissue to reduce galactose-deficient IgA1 production. This agent received FDA approval for IgA nephropathy with proteinuria of 1 gram per day or more and risk of progression, making it the first disease-specific therapy approved for this condition. Felzartamab, an anti-CD38 monoclonal antibody targeting IgA-producing plasma cells, has shown promising proteinuria reduction in phase II trials.

Other Agents

Mycophenolate mofetil has produced inconsistent results, with some studies from Chinese populations suggesting benefit while Western studies have been less convincing. Rituximab has been found to be ineffective for IgA nephropathy, as it does not deplete the IgA-producing mucosal plasma cells that drive disease pathogenesis. Cyclophosphamide combined with steroids is reserved for the crescentic variant of IgA nephropathy presenting with rapidly progressive glomerulonephritis.

<image>Treatment algorithm for IgA nephropathy. Start with diagnosis confirmed by renal biopsy. First tier: optimized supportive care for all patients (ACEi/ARB titrated to maximum dose, SGLT2 inhibitor, BP target <130/80, sodium restriction <2g/day, lifestyle modifications). After 90 days of optimized supportive therapy, reassess proteinuria. If proteinuria <0.75 g/day: continue supportive care with monitoring. If proteinuria 0.75-1.5 g/day: consider targeted-release budesonide (Nefecon) 16 mg/day for 9 months or corticosteroids (TESTING protocol). If proteinuria >1.5 g/day or rapidly declining eGFR: corticosteroids (TESTING reduced-dose protocol) or clinical trial enrollment. For crescentic IgAN with RPGN: pulse methylprednisolone followed by cyclophosphamide. Include emerging therapies panel showing complement inhibitors and anti-CD38 antibodies in development.</image>

IgA Nephropathy Recurrence After Transplant

Histologic recurrence of IgA nephropathy occurs in 30 to 60 percent of allografts by 10 years, though clinically significant graft loss from recurrence affects only 10 to 15 percent over the same period. No proven strategy exists to prevent recurrence. Living related donors with elevated galactose-deficient IgA1 levels represent a theoretical concern, but this is not considered a contraindication to donation. Tonsillectomy, while popular in Japan as a treatment strategy, has no proven benefit in Western populations.

Key Clinical Pearls

• Synpharyngitic hematuria (within 1-2 days of URI) distinguishes IgAN from post-infectious GN (which has a 1-3 week latency period)
• The TESTING trial established that reduced-dose corticosteroids reduce progression risk, but only after optimized supportive care fails to control proteinuria
• Targeted-release budesonide (Nefecon/Tarpeyo) is the first disease-specific therapy approved for IgAN, acting on gut mucosal IgA production
• SGLT2 inhibitors are now considered part of the standard supportive care backbone for IgAN alongside RAAS blockade
• The Oxford MEST-C score provides critical prognostic information; the T score (tubular atrophy/interstitial fibrosis) is the strongest predictor of irreversible renal damage

References

1. Lv J, Wong MG, Hladunewich MA, et al. Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy (TESTING). JAMA. 2022;327(19):1888-1898.
2. Barratt J, Rovin BH, Engstrom-Heidenby E, et al. Budesonide for IgA Nephropathy (NefIgArd). Lancet. 2023;401(10388):1584-1594.
3. Trimarchi H, Barratt J, Cattran DC, et al. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91(5):1014-1021.
4. Rodrigues JC, Haas M, Reich HN. IgA Nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677-686.
5. Barbour TD, Feehally J, Cattran DC. IgA Nephropathy. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 7th ed. Elsevier; 2024.

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