Topic Discussion: Galactose deficient(Gd)-IgA1 as a biomarker in IgA nephropathy after the recent RCTs

The recent wave of IgAN trials has reinforced galactose-deficient IgA1 (Gd-IgA1) as a mechanistic/pharmacodynamic biomarker, but not as a validated diagnostic or monitoring test. Agents targeting "hit 1" of the four-hit pathogenesis model consistently and rapidly lower serum Gd-IgA1: atacicept (ORIGIN 3), sibeprenlimab (VISIONARY/ENVISION), telitacicept, nefecon, and povetacicept all reduce circulating Gd-IgA1 alongside meaningful proteinuria reductions. Nonetheless, KDIGO 2025 states that urine protein excretion remains the only validated early biomarker guiding clinical decisions, and full drug approval is conditioned on the 24-month eGFR slope rather than Gd-IgA1 change. Outside trials, Gd-IgA1's diagnostic and prognostic performance is only moderate and confounded by assay heterogeneity (lectin vs. KM55 vs.glycopeptide LC-MS); it does not reliably separate IgAN from IgA vasculitis, though the Gd-IgA1/C3 ratio shows independent prognostic promise.

A key mechanistic caveat is that BAFF/APRIL blockade suppresses immunoglobulin production broadly, so the Gd-IgA1 fall largely parallels the decline in total IgA. In ORIGIN 3, week-36 reductions were ~68% Gd-IgA1, ~64% total IgA, ~36% IgG, and ~75% IgM — meaning the Gd-IgA1 drop is nearly indistinguishable from a class-wide immunoglobulin reduction. Meta-analyses confirm coordinated declines across IgG, IgA, and IgM. The only selectivity is at the isotype level: anti-APRIL monotherapy (sibeprenlimab) lowers IgA and IgM more than IgG (relative IgG-sparing), reflecting APRIL's role in mucosal IgA class-switching — but this is not true discrimination between the pathogenic glycoform and normally glycosylated IgA1. Trials generally report absolute changes rather than a Gd-IgA1:total-IgA ratio, so a glycoform-selective effect has not been demonstrated.

Finally, the Gd-IgA1 suppression is reversible. In the ENVISION follow-up, Gd-IgA1, total IgA1, and free APRIL all fell by roughly half at month 12 but rebounded toward baseline by month 16 (~4 months after the last dose), implyingthat indefinite therapy is likely needed. Notably, proteinuria reduction persisted somewhat longer than the biomarker rebound, particularly at higher doses. Because the effect is non-depleting, reversibility is considered a class effect, and Tonelli's NEJM editorial explicitly flags Gd-IgA1 rebound after discontinuation as an unresolved issue.

Overall, at this time, Gd-IgA1 functions as a real-time readout of target engagement rather than a validated, glycoform-specific disease monitor or a marker of durable disease modification.

Figure created using AI after input from text

Mentorship in Nephrology: Getting It Right

Nephrology faces a persistent workforce challenge, and mentorship is one of our strongest tools for drawing trainees into the field and keeping them there. A good mentor does more than teach acid-base or dialysis prescriptions. They open doors, protect time, guide career decisions, and model what a sustainable life in nephrology looks like.

But mentorship can also go wrong. Chopra, Edelson, and Saint described "mentor malpractice" in JAMA, and it comes in two forms.

Active malpractice includes the hijacker, who takes over a mentee's project, and the exploiter, who assigns busywork that serves the mentor's goals. The possessor blocks outside collaboration, and the saboteur undermines the mentee's progress.

Passive malpractice is quieter and often more common. The bottleneck sits on manuscripts for months. The world traveler is never available, and the country clubber avoids conflict and so never gives honest feedback.

For a specialty working to recruit, these failures cost us future nephrologists.

The fix starts with clear expectations, regular check-ins, shared authorship agreements, and mentorship teams rather than a single mentor. Mentees can help too, by setting agendas and asking for feedback.

Mentor well. Our field depends on it.

In the NEWS: Is Hemoglobinuria an Underused Marker of Active IgA Nephropathy?

Hematuria is one of the defining clinical features of IgA nephropathy (IgAN), yet contemporary risk assessment remains largely centered on proteinuria and eGFR. Vargas-Brochero and colleagues asked an important question: can the simple presence of blood on urinalysis provide information about ongoing glomerular inflammation?

In this multicenter retrospective study, investigators evaluated 441 patients with biopsy-proven IgAN from four international cohorts between 2015 and 2025. Urinary hemoglobin by dipstick, microscopic hematuria, and proteinuria obtained around the time of biopsy were compared with individual components of the Oxford MEST-C classification.

The findings were striking. Dipstick hemoglobinuria was associated with active inflammatory lesions, including mesangial hypercellularity (M1; OR 1.77), endocapillary hypercellularity (E1; OR 1.75), and crescents (C1/C2; OR 1.57). Microscopic hematuria showed similar, although generally weaker, associations. For the composite of M1, E1, and/or C1/C2 lesions, hemoglobinuria demonstrated the strongest association (OR 2.28), compared with microscopic hematuria (OR 1.36) and proteinuria (OR 1.20).

Importantly, hemoglobinuria and microscopic hematuria were not associated with chronic histologic damage, whereas proteinuria correlated with tubular atrophy/interstitial fibrosis (T1/T2). This distinction suggests that these urinary biomarkers may be capturing different aspects of IgAN biology: hematuria reflecting active glomerular inflammation and proteinuria reflecting, at least partly, accumulated structural injury.

The clinical takeaway is refreshingly simple: don’t ignore the blood on the dipstick. In an era increasingly focused on disease activity and targeted therapies in IgAN, inexpensive and readily available hemoglobinuria may provide complementary information beyond proteinuria and eGFR when assessing ongoing disease activity.

Read the Kidney International article