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

Detective Nephron: Next venture

 August 2026 issue for Detective Nephron

Topic Discussion: Futball and the Kidney ( soccer)

What happens to the kidneys during a soccer match?

With the 2026 FIFA World Cup approaching, it's the perfect time to remember that soccer doesn't just challenge the heart and muscles—it also places unique physiological stress on the kidneys. A review in Kidney Medicine explores the fascinating intersection of sports nephrology and soccer. 

⚽ Top 5 Kidney Takeaways

Most kidney changes are physiologic—not pathologic.
Transient rises in serum creatinine, exercise-induced proteinuria, microscopic hematuria, and reductions in eGFR are common after intense matches and usually resolve within 24–72 hours.

Hydration is kidney protection.

Maintaining hydration before, during, and after matches minimizes tubular stress and limits increases in biomarkers such as NGAL and KIM-1, especially during play in heat.

Creatinine isn't the whole story.
Because muscle injury elevates serum creatinine, biomarkers such as cystatin C, NGAL, and KIM-1 may better distinguish physiologic adaptation from true kidney injury in athletes.

Avoid unnecessary NSAIDs.
Dehydration, heat stress, rhabdomyolysis, and NSAID use together substantially increase the risk of acute kidney injury during competition.

Soccer remains kidney-safe for most athletes.
With appropriate hydration, individualized risk assessment, and avoidance of nephrotoxins, even many athletes with CKD, a solitary kidney, or a kidney transplant can safely participate.

Bottom line: Soccer challenges the kidneys—but in healthy athletes these changes are usually adaptive, transient, and reversible. Understanding these physiologic responses helps clinicians avoid overdiagnosis while recognizing the rare athlete who truly needs evaluation.

Figure from paper

Consult Rounds: Mantle Cell Lymphoma and the Kidney

Mantle Cell Lymphoma Isn't Just Renal Infiltration

In a paper published in KI Reports, various GNs were reported with Mantle Cell lymphoma. When we think of kidney disease in mantle cell lymphoma (MCL), we often think about direct lymphomatous infiltration. This multicenter series reminds us that immune-mediated glomerular diseases are actually common and frequently improve with lymphoma-directed therapy.

Study Highlights

• 30 patients with MCL who underwent kidney biopsy from multiple centers.

• 20 had active MCL at biopsy.

• Among those with active disease:

  • 70% had kidney lesions attributable or potentially attributable to MCL.

  • 55% had immune complex (IC) or complement-mediated glomerular disease.

  • 40% had renal lymphomatous infiltration, often coexisting with glomerular lesions.

Interestingly, renal Pathology Was Remarkably Diverse. The spectrum included:

• PGNMID (including IgG3κ cases)

• C3 glomerulonephritis

• Secondary membranous nephropathy

• Lupus-like immune complex GN

• Tubular basement membrane immune deposits

• Concurrent lymphomatous infiltration in many patients.

Perhaps the most important finding: Patients with PGNMID, C3GN, and membranous nephropathy who received lymphoma-directed therapy experienced remission of both their hematologic disease and kidney disease, with marked improvements in creatinine and proteinuria.

Unlike many monoclonal gammopathy-associated kidney diseases, most glomerular lesions were polyclonal rather than monoclonal, suggesting that immune dysregulation and complement activation—rather than direct deposition of a circulating monoclonal protein—may drive kidney injury in MCL.

In summary, Kidney injury in MCL extends far beyond direct lymphoma infiltration.  Consider kidney biopsy in MCL patients with AKI, proteinuria, or hematuria.  Successful treatment of the lymphoma can result in remission of the glomerular disease, emphasizing the importance of multidisciplinary care between nephrology, pathology, and hematology.

Consult Rounds: Histotripsy associated AKI

 

Histotripsy is an emerging non-invasive, non-thermal ablative technology that uses focused ultrasound pulses to mechanically destroy tumors through acoustic cavitation. Approved by the FDA in late 2023 for treatment of liver tumors, histotripsy has generated excitement because it can fragment tissue without surgical incisions, ionizing radiation, or traditional thermal injury. Early studies have also suggested potential downstream immunomodulatory effects beyond localized tumor destruction.

During the procedure, patients typically undergo general anesthesia in an interventional radiology suite or hybrid operating room. Real-time ultrasound guidance is used to localize the lesion and define the treatment field. High-amplitude ultrasound pulses generate dense cavitation bubble clouds that rapidly expand and collapse, mechanically fractionating tissue into acellular debris while largely sparing surrounding structures. Treatment is delivered sequentially in a raster-like pattern across the lesion with continuous imaging feedback.( see above figure created via AI)

While the oncology potential of histotripsy is substantial, nephrologists should be aware of a possible emerging complication: histotripsy-associated acute kidney injury (H-AKI). In a recent brief report published in KI Reports, a patient developed AKI with hematuria shortly after hepatic histotripsy in the absence of alternative clear insults, with improvement following hydration and supportive care.

To further explore whether this represented an isolated event or a broader signal, post-marketing review of the FDA MAUDE database identified additional cases of renal impairment following hepatic histotripsy. Reported patients were often older females with larger treatment volumes (>90 cc). Some required dialysis, while others recovered with conservative management and intravenous fluids. However, MAUDE data remain hypothesis-generating and limited by underreporting, lack of adjudication, and incomplete clinical detail.

Additional support for this phenomenon comes from an abstract presented at the Society of Interventional Radiology describing multiple cases of histotripsy-induced AKI. Interestingly, several reports described dark or discolored urine, raising the possibility of pigment-mediated tubular injury.

At present, no biopsy-proven mechanism has been reported. Proposed pathophysiologic mechanisms include hemolysis with pigment nephropathy, release of cellular debris after extensive tissue fractionation, hemodynamic injury, inflammatory cytokine release, or immune-mediated interstitial injury. Larger treatment fields may increase systemic exposure to hemoglobin, heme pigments, and intracellular contents.

Why does this matter? Histotripsy is rapidly expanding beyond hepatic tumors into renal and other solid organ malignancies. As use increases, nephrologists, oncologists, and interventional radiologists should recognize AKI as a potential procedural complication requiring early identification and supportive management. Future studies are needed to better define incidence, mechanisms, biomarkers, and preventive strategies for H-AKI.