GN in Ten

Board Review Bonus 7: Membranous Nephropathy
In this "Board Review Bonus" (BRB) episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain deliver a high-yield clinical overview of membranous nephropathy (MN)—a classic, board-favorite cause of nephrotic syndrome. Utilizing a real-world case of a 50-year-old male presenting with heavy proteinuria and severe hypoalbuminemia, they walk through diagnostic dilemmas, pathological clues, and the modern therapeutic landscape. Whether you are studying for the boards or looking to "class-switch" your clinical knowledge from IgG1 to IgG4, this bite-sized episode is packed with essential clinical pearls.
Key Topics Covered:

Epidemiology & Biopsy Basics: Identifying MN as one of the most common causes of adult nephrotic syndrome. The hosts break down classic pathology features: diffuse GBM thickening on light microscopy, "spikes" on silver stain, granular IgG and C3 immunofluorescence, and subepithelial dense deposits on EM.
The Antigen Revolution: A review of how the 2009 discovery of anti-PLA2R antibodies on podocytes transformed the diagnosis of primary MN. They also highlight newer antigens to know for the boards, including NELL-1 (associated with malignancy, medications, and lipoic acid), THSD7A (associated with malignancy), and EXT1/EXT2 (associated with lupus).
Investigating Secondary Causes: Why age-appropriate malignancy screening, medication reviews, and infectious workups (syphilis, hepatitis B and C) are essential even in PLA2R-positive cases. Key biopsy clues like "full house" staining or endothelial tubuloreticular inclusions can help tip you off to a secondary etiology.
The "Koyal-Kenar" Risk Stratification: Why tracking immunological remission via anti-PLA2R titers is often far more predictive than following proteinuria alone. The hosts outline when to initiate immunosuppression based on GFR decline, severe proteinuria/complications, or stable/rising anti-PLA2R titers.
Conservative Therapy (The CKD Toolkit): Standard management including low-sodium diets, maximal RAAS blockade, statins (mindful of CNI interactions), SGLT2 inhibitors, and prophylactic anticoagulation (using apixaban or warfarin) when albumin drops below 2.0–2.5 g/dL.
The Immunosuppressive Toolkit: Navigating the "big three" regimens: the highly effective but complex 6-month Modified Ponticelli Regimen, first-line Rituximab (backed by the MENTOR trial), and Calcineurin Inhibitors (useful as a bridge, but limited by high relapse rates). Plus, a sneak peek at obinutuzumab (the Majesty trial) for deeper B-cell depletion.
Recommended Literature:

Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy
Fernández-Juárez G, Rojas-Rivera J, van de Logt AE, et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy. 
Scolari F, Delbarba E, Santoro D, et al. Rituximab or cyclophosphamide in the treatment of membranous nephropathy: the RI-CYCLO randomized trial.
The MAJESTY Trial (Obinutuzumab vs Tacrolimus in Primary Membranous Nephropathy): ClinicalTrials.gov Identifier: NCT04629248.

Board Review Bonus 6: Alport Syndrome
 In this "Board Review Bonus" (BRB) episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain provide a comprehensive clinical overview of hereditary nephritis—also known as Alport syndrome—a complex genetic condition with critical renal and extrarenal implications. From a sneaky real-world case of an 18-year-old female presenting with isolated microscopic hematuria to classic textbook syndromic features , our hosts break down the essential knowledge required for both board preparation and clinical practice.

The discussion moves beyond the classic X-linked male phenotype to explore autosomal varieties and why thin basement membrane disease (TBMD) is increasingly viewed as part of the Alport spectrum rather than a purely benign entity. Dr. Jain and Dr. Jhaveri emphasize critical management strategies, highlighting why an accurate diagnosis is vital to protect patients from receiving unnecessary and ineffective immunosuppressive therapies.

Key Topics Covered:
The Hematuria Differential: Evaluating a young patient with a family history of hematuria, prioritizing Alport syndrome, thin basement membrane disease, and IgA nephropathy.
Genetics and Inheritance Patterns: A detailed look at mutations in the alpha 3, 4, and 5 chains of type IV collagen, spanning X-linked, autosomal recessive, and autosomal dominant variants.
Clinical and Extrarenal Manifestations: Identifying the classic trio of kidney involvement, high-pitched sensorineural hearing loss, and ocular abnormalities like anterior lenticonus.
Biopsy and Pathology Pearls: Differentiating between simple glomerular basement membrane (GBM) thinning and advanced longitudinal splitting ("basket-weave" lamination) on electron microscopy, alongside the utility of pediatric skin biopsies.
Clinical Management & Pitfalls: Navigating first-line RAAS inhibition and SGLT2 inhibitors while strictly avoiding immunosuppressive regimens for secondary FSGS lesions.
Transplantation Outcomes: Understanding why Alport syndrome does not recur post-transplant, balanced against the 3% to 4% risk of developing de novo anti-GBM disease in the allograft.
Recommended Literature:
Consensus statement on guidelines for the care of children and adolescents with Alport syndrome.
Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.
Alport Syndrome: Classification and Management

Episode 5: Board Review Bonus: Renal Amyloidosis

In this "Board Review Bonus" (BRB) episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain provide a comprehensive clinical overview of amyloidosis—a complex and often enigmatic disease with significant renal implications. From the initial "mushy, smudgy" appearance on light microscopy to the precise measurements of electron microscopy, our hosts break down the essential knowledge required for both board preparation and clinical practice.
The discussion moves beyond the common AL and AA variants to explore rare types like LECT2 and the hereditary forms. Dr. Jain and Dr. Jhaveri emphasize that "the tissue is the issue," highlighting the diagnostic necessity of biopsying the affected organ and the critical role of mass spectrometry in directing therapy.
Key Topics Covered:

Classification of Amyloidosis: A detailed look at AL, AA, LECT2, and the hereditary variants including ATTR, fibrinogen A alpha-chain, and Apolipoprotein.
The Diagnostic Workup: Understanding the utility of Congo red staining, the significance of birefringence, and the institutional variability of fat pad biopsies.
Electron Microscopy (EM) Pearls: A guide to differentiating amyloid fibrils from mimics such as fibrillary GN, immunotactoid GN, and cryoglobulinemia based on diameter and arrangement.
Clinical Management: Navigating the multidisciplinary approach between nephrology, hematology, and cardiology, including the nuances of RAAS inhibition and diuretic therapy in proteinuric patients.
Transplantation Outcomes: Evaluating recurrence rates and survival benefits for different amyloid types post-kidney transplant.

Recommended Resources and Literature:
Visual Aid: Concept Map: Causes of Renal Amyloidosis – A comprehensive resource for classifying amyloid variants and their underlying triggers (via NephronPower).
Dandona P, et al. The amyloidoses: clinical features, diagnosis and treatment. Methodist Debakey Cardiovasc J. 2012 Jul-Sep;8(3):3-7. PMC3487569
Panichella G, et al. Heart Failure Management in Cardiac Amyloidosis: Towards a Paradigm Shift. Heart Fail Rev. 2024. PMC12308146
Moreno-Martínez P, et al. LECT2-associated renal amyloidosis (ALECT2): A case report. Nefrologia. 2018 Jan-Feb;38(1):97-99. PMID: 29254900
Benson MD, et al. Hereditary renal amyloidosis associated with a mutant fibrinogen alpha-chain. Nat Genet. 1993 Mar;3(3):252-5. PMID: 8097946

In this episode, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain are joined by Dr. Matt Sparks (co-creator of NephMadness) and Dr. Aarushi Varshney to discuss the evolving landscape of C3 Glomerulopathy (C3G). The conversation highlights the shift from traditional electron microscopy-based classifications to modern immunofluorescence-based diagnosis, as well as the groundbreaking arrival of two new FDA-approved targeted therapies.
The NephMadness Matchup

This episode focuses on the C3G bracket pitting two critical aspects of C3G against each other:
Team Diagnosis: Focusing on the challenges of distinguishing C3G from infection-related GN or monoclonal gammopathy.
Team Treatment: Highlighting the new era of factor B and C3 inhibitors that are revolutionizing patient outcomes.

Key Takeaways

1. Challenges in Diagnosis
The "Two Orders of Magnitude" Rule: Modern diagnosis is based on immunofluorescence (IF) showing C3 deposition that is at least two orders of magnitude greater than any other immunoglobulin.
C3G vs. PIGN: It can be difficult to distinguish C3G from Post-Infectious Glomerulonephritis (PIGN). Clinical clues include patient age, the persistence of low C3 levels after infection resolution, and the presence (or absence) of sub-epithelial humps on pathology.
The Role of Monoclonal Gammopathy: In older patients, it is critical to rule out monoclonal gammopathy (using SPEP and free light chain assays) as a driver of complement activation.

2. The New Therapeutic Era

The panel discussed two landmark drugs that have recently shifted the C3G treatment paradigm:
Iptacopan: An oral factor B inhibitor that showed a 30% reduction in proteinuria at six months in the APPEAR trial.
Pegcetacoplan: A subcutaneous infusion (twice weekly) C3 inhibitor that demonstrated a nearly 70% reduction in proteinuria and stabilization of eGFR in the VALIANT trial.
A "Hammer" Approach: Pegcetacoplan is described as a "larger hammer" because it acts at the crux of all three complement pathways (Classical, Lectin, and Alternative).

3. Safety & Monitoring
Vaccination: Because these drugs inhibit the complement cascade, patients MUST be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae at least two weeks before starting therapy.
Prophylaxis: If urgent treatment is required, patients should start prophylactic antibiotics (such as Penicillin, Augmentin, or Ciprofloxacin).

Resources & Studies Mentioned
NephMadness: The annual educational "tournament" in nephrology that inspired this discussion.
The APPEAR Trial (Iptacopan): Investigated the efficacy of the oral factor B inhibitor in patients with C3G.
The VALIANT Trial (Pegcetacoplan): Evaluated the C3 inhibitor in patients with C3G and primary immune complex MPGN, including post-transplant patients.
The hosts and guests of this GN in 10 episode do not have any disclosures to make relevant to the content of this episode.

It’s the "New England Journal of IgA" these days, and we’re just living in it! In this special NephMadness edition of GN in Ten, hosts Dr. Kenar Jhaveri and Dr. Koyal Jain are joined by NephMadness co-creator Dr. Matt Sparks and Duke Fellow Dr. Ale Tomasi to break down the heavy hitters in the IgA Nephropathy bracket. Matt’s dog also joins us for a special, possibly biased cameo.
We’re moving past "ACE first, think later" and diving into the upstream battle: B-cell modulators (BAFF/APRIL inhibitors) versus Complement inhibitors. Whether you’re team "Hit Zero" or team "Alternative Pathway," this episode covers the latest trial data from ORIGIN, VISIONARY, and APPLAUSE to help you fill out your bracket. 

The "Hit Zero" Hypothesis

While we all know the classic four-hit hypothesis of IgAN, new therapies are targeting even further upstream—what some are calling "Hit Zero." 
Pathophysiology Recap: IgAN starts with galactose-deficient IgA1 (Hit 1), leading to autoantibody production (Hit 2), immune complex formation (Hit 3), and mesangial deposition/damage (Hit 4). 
B-Cell Modulators: These drugs target BAFF (B-cell activating factor) and/or APRIL (a proliferation-inducing ligand) to reduce the production of those pesky autoantibodies right at the source. 

The B-Cell Contenders: Sibeprenlimab & Atacicept

Sibeprenlimab ("Sibi"): A monoclonal antibody directed at APRIL. The Data: Showed a 50% reduction in proteinuria at interim analysis and a nearly 98% reduction in APRIL levels. 
Status: Currently has conditional FDA approval. 

Atacicept: A fusion protein that dual-blocks both BAFF and APRIL. The Data (ORIGIN trials): Demonstrated a 45.7% proteinuria reduction at 36 weeks and, notably, stabilization of eGFR slope in long-term follow-up. 
Pronunciation Debate: Is it "Attack-a-cept" or "A-tassi-cept"? The investigators say "Attack," because it’s out for blood. 

The Complement Contender: Iptacopan

Mechanism: A factor B inhibitor that specifically targets the alternative complement pathway, which is increasingly recognized as a key driver of IgAN damage. 
The APPLAUSE Study: This oral, twice-daily pill showed a 38% reduction in proteinuria at nine months. 
Safety First: Because complement blockade increases the risk of infections from encapsulated bacteria, patients must be up to date with vaccinations for meningitis, streptococcal and pneumococcal infections. 

The Verdict: Who Wins the Bracket?

Tune in to find out what our experts think… then fill out your own bracket!

References

Atacicept

Lafayette R, Barbour SJ, Brenner RM, Campbell KN, Doan T, Eren N, Floege J, Jha V, Kim BS, Liew A, Maes B, Pal A, Pecoits-Filho R, Phoon RKS, Rizk DV, Suzuki H, Tesař V, Trimarchi H, Wei X, Zhang H, Barratt J; ORIGIN Phase 3 Trial Investigators. A Phase 3 Trial of Atacicept in Patients with IgA Nephropathy. N Engl J Med. 2026 Feb 12;394(7):647-657. doi: 10.1056/NEJMoa2510198. Epub 2025 Nov 6. PMID: 41196369.
Lafayette R, Barbour S, Israni R, Wei X, Eren N, Floege J, Jha V, Kim SG, Maes B, Phoon RKS, Singh H, Tesař V, Lin CJF, Barratt J. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy. Kidney Int. 2024 Jun;105(6):1306-1315. doi: 10.1016/j.kint.2024.03.012. Epub 2024 Mar 27. PMID: 38552841.
Sibeprenlimab

Perkovic V, Trimarchi H, Tesar V, Lafayette R, Wong MG, Barratt J, Suzuki Y, Liew A, Zhang H, Carroll K, Jha V, Quevedo A, Han SH, Praga M, Chacko B, Sahay M, Cheung CK, Kooienga L, Walsh M, Xia J, Fajardo C, Shah L, Hafkin J, Rizk DV; VISIONARY Trial Investigators Group. Sibeprenlimab in IgA Nephropathy - Interim Analysis of a Phase 3 Trial. N Engl J Med. 2026 Feb 12;394(7):635-646. doi: 10.1056/NEJMoa2512133. Epub 2025 Nov 8. PMID: 41211929.
Mathur M, Barratt J, Chacko B, Chan TM, Kooienga L, Oh KH, Sahay M, Suzuki Y, Wong MG, Yarbrough J, Xia J, Pereira BJG; ENVISION Trial Investigators Group. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. N Engl J Med. 2024 Jan 4;390(1):20-31. doi: 10.1056/NEJMoa2305635. Epub 2023 Nov 2. PMID: 37916620; PMCID: PMC7615905.
Iptacopan

Perkovic V, Barratt J, Rovin B, Kashihara N, Maes B, Zhang H, Trimarchi H, Kollins D, Papachristofi O, Jacinto-Sanders S, Merkel T, Guerard N, Renfurm R, Hach T, Rizk DV; APPLAUSE-IgAN Investigators. Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy. N Engl J Med. 2025 Feb 6;392(6):531-543. doi: 10.1056/NEJMoa2410316. Epub 2024 Oct 25. PMID: 39453772.
Zhang H, Rizk DV, Perkovic V, Maes B, Kashihara N, Rovin B, Trimarchi H, Sprangers B, Meier M, Kollins D, Papachristofi O, Milojevic J, Junge G, Nidamarthy PK, Charney A, Barratt J. Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int. 2024 Jan;105(1):189-199. doi: 10.1016/j.kint.2023.09.027. Epub 2023 Oct 31. PMID: 37914086. 

The hosts and guests of this GN in 10 episode do not have any disclosures to make relevant to the content of this episode.