Managing IgA Nephropathy

Main Ideas and Clinical Lessons

1. IgA Nephropathy Is Common, Variable, and an Active Area of Therapeutic Research

• IgA nephropathy (IgAN) is a leading cause of glomerular disease. It can range from mild urinary abnormalities to rapidly progressive kidney injury.
• Proteinuria is a major indicator of progression and an important treatment target. The speakers described a shift toward treating lower levels of proteinuria: persistent proteinuria above about 0.5 g/day is considered concerning, with a longer-term goal of reducing it to below 0.5 g/day, ideally below 0.3 g/day.
• Treatment should address both the underlying IgAN process and broader chronic kidney disease (CKD) pathways, such as proteinuria, inflammation, fibrosis, and nephron loss.

2. Case Presentation: Acute Kidney Findings After a Respiratory Infection

The case involved a young woman who developed visible blood in her urine shortly after a brief upper respiratory illness, followed by facial and leg swelling, reduced urine output, and high blood pressure. Initial testing showed kidney dysfunction, hematuria, and proteinuria.

• The clinical syndrome was considered acute nephritic syndrome, characterized by hematuria, reduced urine output, edema, and hypertension.
• The patient also had substantial proteinuria—about 3.1 g/day—with low serum albumin. This made the presentation less typical for straightforward IgAN and raised concern for other or overlapping processes.
• The main diagnostic possibilities included:
  • IgA nephropathy, particularly given the close timing between the respiratory illness and hematuria.
  • Infection-related glomerulonephritis, including IgA-dominant infection-related disease.
  • Lupus nephritis, which remains important to consider in a young woman, even without obvious systemic symptoms.
• Normal complement levels and negative ANA, anti-dsDNA, ANCA, and anti-GBM tests helped narrow the differential, but tissue diagnosis was still needed.
• A previous uncomplicated full-term pregnancy was taken as evidence that major kidney dysfunction was less likely to have been present three years earlier.

3. Diagnostic Reasoning and Interpretation

• Glomerular hematuria: Dysmorphic red blood cells, acanthocytes, and red blood cell casts support a glomerular source. Phase-contrast microscopy can help identify dysmorphic cells; an RBC cast can also be recognized on routine microscopy.
• Frothy urine is not diagnostic of proteinuria. Other substances can also make urine appear frothy.
• Edema can arise through different mechanisms:
  • In nephritic syndrome, it is mainly associated with reduced filtration and sodium and water retention.
  • In nephrotic syndrome, low blood albumin and/or renal sodium retention can contribute.
• The biopsy showed mesangial hypercellularity and expansion, focal endocapillary hypercellularity, segmental sclerosis in some glomeruli, and acute tubular injury with RBC casts. Immunofluorescence showed strong mesangial IgA staining with C3 staining.
• The biopsy was interpreted in the session as IgAN, with an Oxford MEST-C score of M1 E1 S1 T0 C0. The lack of electron microscopy was highlighted as a limitation:
  • Electron microscopy can help distinguish IgAN from infection-related GN, where subepithelial “humps” may be seen.
  • Given the heavy proteinuria, it could also assess podocyte foot-process effacement and help identify a coexisting podocytopathy, such as minimal change disease or FSGS.
  • The speakers argued that light microscopy and immunofluorescence alone may not be enough for full interpretation when the clinical picture is atypical.
• IgA deposits can sometimes be incidental or “bystander” findings. They must be interpreted alongside the clinical picture, biopsy findings, and possible secondary causes, including chronic liver disease.

4. Risk Assessment and Treatment Principles

The speakers stressed the following sequence and considerations:

• First, exclude secondary causes of IgA deposition or IgAN-like disease.
• Use risk tools and biopsy findings to inform prognosis, but do not treat a risk score or Oxford score as a direct prescription for a particular therapy.
• Proteinuria is a key practical marker for treatment decisions; blood pressure, kidney function, and biopsy findings also inform prognosis.
• In IgAN, acute kidney injury may result from:
  • Tubular obstruction or injury associated with RBC casts during gross hematuria.
  • Crescents and rapidly progressive glomerular inflammation.
• Supportive CKD treatment discussed includes:
  • Blood-pressure control and renin–angiotensin system (RAS) blockade.
  • SGLT2 inhibitors.
  • Disease-specific treatment where appropriate, rather than waiting several months on supportive care alone in every patient.
• Systemic corticosteroids remain a possible option when disease-specific targeted-release budesonide is unavailable or unaffordable, but their use should be individualized. The discussion emphasized their systemic risks and the importance of considering kidney function and patient risk factors.
• The group distinguished targeted-release budesonide studied in clinical trials from the controlled-release or generic gut-directed formulations available locally. They cautioned that the formulations may not have the same release characteristics or evidence base, and that even gut-directed budesonide can have systemic effects.
• Mycophenolate mofetil (MMF) has evidence mainly from East Asian populations. The speakers said there is not yet strong trial evidence to support routine use across other populations. An Indian platform trial was noted as ongoing.
• For clinically rapidly progressive disease, treatment may differ from routine IgAN management. The panel distinguished clinically progressive disease from the mere presence of crescents on biopsy.

5. New and Emerging Treatments Discussed

The treatment framework presented has two complementary pathways:

• Disease-modifying therapies target the IgAN immune process, including abnormal IgA production, B cells, plasma cells, or complement.
• CKD-pathway therapies target proteinuria, inflammation, fibrosis, and kidney-function decline.

The discussion covered:

• Targeted-release budesonide (Nefecon/NefIgArd): Designed to act locally in the terminal ileum and gut-associated lymphoid tissue. Trials showed reduced proteinuria and a benefit in eGFR slope. The panel noted that this formulation was not available locally and that local controlled-release products may differ.
• APRIL and BAFF pathway inhibitors: These aim to reduce the production or survival of cells involved in generating pathogenic IgA. Sibeprenelimab was discussed as having encouraging interim proteinuria results. Levels of disease-associated IgA rose again after treatment stopped, suggesting that ongoing or repeated treatment may be needed. Other agents mentioned included atacicept, telitacicept, and povetacicept, with studies ongoing.
• Plasma-cell-targeting treatment: Felzartamab, an anti-CD38 antibody, was discussed as an investigational option. Rituximab has not shown clear benefit in an IgAN randomized trial; one possible explanation offered was that relevant mucosal plasma cells may not express CD20.
• Complement inhibition: Iptacopan was highlighted as an investigational/approved option in the lecture’s account, with other complement pathways also being studied.
• Sparsentan: A dual endothelin–angiotensin receptor antagonist. The PROTECT trial was described as showing sustained proteinuria reduction and improved eGFR slope compared with irbesartan. Potential issues include hyperkalemia, edema, dizziness, liver monitoring, and pregnancy prevention; availability may be limited.
• Other CKD-pathway drugs: Atrasentan and finerenone were mentioned as therapies under study in IgAN.
• CAR-T therapy: Described as experimental, with practical limitations including cost, the need for specialized treatment and hospitalization, and risks such as cytokine-release syndrome.

Because most new drugs have been compared with placebo rather than directly with one another, the panel emphasized that head-to-head evidence is lacking and encouraged enrollment in clinical trials when possible.

6. Broader Understanding of IgAN

The update revisited the “four-hit” model and described additional mechanisms:

• Mucosal immune activity, particularly in the gut and upper respiratory tract, may contribute to abnormal IgA production.
• BAFF and APRIL support B-cell and plasma-cell survival and differentiation.
• Autoantibodies, immune-complex formation, complement activity, and mesangial interactions contribute to kidney inflammation.
• The gut, bone marrow, and possibly the kidney itself may serve as important sites for relevant immune-cell activity.
• These processes can lead to glomerular inflammation, tubulointerstitial scarring, nephron loss, and kidney failure.

Speakers and Sources Featured

• Dr. Debrup Sengupta — case presenter.
• Dr. Arpita Roy Chaudhury — examiner; her name is also rendered as “Arpita Ray Chaudhury” in the captions.
• Dr. Suceena/Sakshina Alexander — discussant; the auto-generated captions vary in the spelling of her name.
• Dr. Anuradha Raman — expert for the session and closing commentator.
• Dr. Vijay Kher — convener and session chair.
• Dr. (Lt. Gen.) P. P. Varma — convener; he gave opening remarks and later left for another meeting.
• Puneet — opening host/moderator.
• Dr. Jean Berger — cited as the pathologist associated with the original description of IgA nephropathy; the captions render the name inaccurately.
• Dr. Mani — referred to during discussion of IgA deposits found in kidney donors/autopsy material.

Clinical evidence and trials cited included NefIgArd, VISIONARY, PROTECT, ALIGN, and the Ruby 3 study, as well as KDIGO guidance and an Indian platform trial.