Next Detective Nephron

 Enjoy the journey of hypomagnesemia in the next DN in ASN Kidney News.

In the NEWS: Unmasking PGNMID: Is it Truly Monoclonal, or Are We Misclassifying Kidney Disease?

 

    Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a severe kidney disease, traditionally classified under Monoclonal Gammopathy of Renal Significance (MGRS). This classification implies that the kidney damage is caused by a single, abnormal B-cell or plasma cell clone producing a "monoclonal" antibody. However, a long-standing puzzle in nephrology has been the surprisingly low rate at which these supposed disease-causing clones are actually detected in PGNMID patients. This discrepancy has fueled a debate: is PGNMID always truly monoclonal, or are we sometimes misattributing its cause?

    A recent study published in Kidney International, led by Javaugue, Pascal, and colleagues, delves into this question using advanced diagnostic tools. They analyzed 56 PGNMID patients, employing highly sensitive immunoglobulin repertoire sequencing (RACE-RepSeq) on bone marrow samples and specialized immunofluorescence on kidney biopsies to scrutinize the nature of the deposited immunoglobulins. The findings challenge conventional understanding. Only 23% of the patients had a detectable bone marrow clone consistent with their kidney deposits. The predominant subtype, PGNMID-IgG3, accounted for 73% of cases and was the main reason for the low clone detection rate; a mere 9.8% of these IgG3 cases showed a clonal B-cell proliferation. 

Crucially, in clone-negative PGNMID-IgG3 kappa patients, kidney biopsies revealed that the immunoglobulin deposits were *oligoclonal* or *polyclonal*, not truly monoclonal as the "monotypic" appearance on standard immunofluorescence might suggest.

Patients with clone-negative PGNMID showed distinct characteristics compared to clone-positive patients. Although diagnosed younger, they presented with more severe symptoms at diagnosis, including significantly higher proteinuria, but, interestingly, showed a lower prevalence of hypocomplementemia. Since IgG3 is the most frequent isotype and is known to be highly effective to bind and activate complement components, this finding is somehow surprising. However, compared to clone-positive patients with an elevated circulating monoclonal Ig, serum IgG3 levels in this subgroup remain normal which could explain the absence of hypocomplementemia. The study also hinted at potential infectious triggers in clone-negative cases, observing increased IgG1 and highly mutated light chain repertoires.

This research strongly suggests that PGNMID is a heterogeneous condition. The authors conclude that most PGNMID-IgG3 cases are driven by oligoclonal or polyclonal IgG3 production and do not arise from an underlying monoclonal B-cell disorder. They propose that such cases should no longer be classified as MGRS, and suggest the term "proliferative glomerulonephritis with monotypic deposits" to accurately reflect their origin. This distinction is critical, as it has profound implications for how these patients are diagnosed and, ultimately, treated. The study underscores the power of advanced molecular techniques in refining our understanding and management of complex kidney diseases.

In the News: B cell and plasma cell therapies in Glomerular Diseases

Glomerular diseases often result from loss of immune tolerance, leading to the production of autoantibodies by plasmablasts/plasma cells. Besides secreting antibodies, B cells contribute to T cell activation through antigen presentation and the secretion of pro-inflammatory cytokines. Standard immunosuppression works broadly but has many side effects, and many patients remain refractory. Thus, there is growing interest in therapies that more precisely target B cells and plasma cells. This review in JASN 2025 really is a very nicely done summary of the topic. 

B cells develop through naïve, activated, memory, plasmablast, to plasma cell stages. Memory B cells and long-lived plasma cells are particularly important in sustaining autoantibody production. 

Differential expression of surface markers (e.g. CD20 present on many B cells but lost in plasma cells) and dependency on survival signals (such as BAFF, APRIL) define what makes some cells resistant to certain therapies. 

Some challenges are that some plasma cell populations are long-lived and reside in protected niches (e.g. bone marrow), making them resistant to many therapies. Risk of depleting beneficial B cell subsets (e.g. those with regulatory functions). Heterogeneity of disease: different glomerular diseases (IgA nephropathy, lupus nephritis, membranous nephropathy, vasculitis etc.) have varying dependence on B cells vs plasma cells.

Therapies targeting B cells and plasma cells have shown promise in trials for various glomerular diseases. See the table below. Novel tools (like CAR-T, bispecifics) may help overcome resistance and target plasma cells more effectively.

Lupus Nephritis has trials ongoing with BAFF inhibition, Anti CD20+BAFF, BTK inhibitor, Anti CD38, CAR-T and bispecifics.  ANCA vasculitis has trials ongoing in Anti CD20 with BAFF-APRIL, and CAR-T.  Membranous Nephropathy has trials ongoing in anti-CD-20, BAFF, BTK inhibitors and Anti CD-38.  MCD/FSGS has trials ongoing in Anti CD-20 and BTK inhibitors. IgAN has trials in APRIL, APRIL+BAFF, Anti CD38 and CAR-T as well. 

Table: Therapies Targeting B-Cell and Plasma Cell Lineages in Glomerular Disease

Target / Stage	Examples of Therapeutics	Notes
Naïve / Mature B Cells	Anti-CD20 mAbs (rituximab, obinutuzumab, ofatumumab)	Deplete most circulating B cells, but not plasma cells
B Cell Survival Signals	BAFF inhibitors (belimumab), BAFF/APRIL dual inhibitors (telitacicept)	Block trophic support for B cells and plasmablasts
BCR Signaling	BTK inhibitors (ibrutinib, acalabrutinib)	Reduce activation and differentiation
Plasmablasts / Short-lived PCs	Proteasome inhibitors (bortezomib, carfilzomib)	Induce apoptosis of antibody-secreting plasmablasts
Long-lived Plasma Cells	Anti-CD38 mAbs (daratumumab, isatuximab); anti-BCMA agents	Direct depletion, even in bone marrow niches
Novel Cellular Immunotherapy	CAR-T cells (anti-CD19, anti-BCMA); bispecific T-cell engagers	Potent but experimental; risk of profound immunosuppression
Regulatory B Cells (Bregs)	Indirectly affected by the above agents	Their depletion may worsen immune dysregulation—needs careful monitoring

KDIGO- 2025 IgAN Clinical Practice Guidelines

 Sept 2025- KDIGO released yet another IgAN Guidelines. The last one was in 2021. Since 2021, several new trials were published with novel agents to be used in IgAN-- from Nefecon, Sparsenten, Atrasenten and Iptacopan.  Which ones made this new guideline?

This is the main figure from the guidelines.

The key takeaways

1. In all patients, treatment of the immunological side of IgAN and the CKD side, at the same time
2. Addition of Nefecon as an alternative to Steroids
3. Addition of DEARA and SGLT2i to the main CKD treatment option.
4. Lower proteinuria goal of 0.5g/day or lower and ideally 0.3g/day. and a stable eGFR 
5. Early renal biopsy encouragement
6. Still consider clinical trials in the right cases. 

Few misses

1. Pure endothlin antagonists -- will they have a role?
2. Why did complement inhibition not make this cut... perhaps waiting for long-term data
3. APRIL inb soone to be approved and may even add a dent to this strategy above.

Topic Discussions: Auto antibodies in diffuse podocytopathies

Recent advances have reshaped how we view nephrotic syndrome moving from descriptive pathology to a mechanism-based model. A growing body of evidence shows that circulating autoantibodies against key slit diaphragm proteins—nephrin, podocin, and Kirrel1—play a central role in many cases of autoimmune podocytopathy. This was also confirmed in pediatric literature. 

These discoveries promise earlier, less invasive diagnosis and more precise, personalized treatment.

Yet, translating these insights into clinical practice is far from straightforward. The antibodies are often present at very low or transient levels, disappearing into the urine during active disease. Their titers fluctuate with relapses and remissions, complicating the timing of tests. Moreover, NS is heterogeneous: while many patients have anti-nephrin antibodies, others harbor antibodies to podocin or Kirrel1, and some exhibit overlapping profiles through “epitope spreading.”

Technical challenges also hamper detection. Assay performance depends on antigen fragment choice, expression system, and protein modifications—especially for the heavily glycosylated nephrin. To improve reliability, researchers emphasize combined strategies, pairing ELISA with high-resolution biopsy techniques like super-resolution microscopy.

The article proposes a roadmap: develop multiplex assays, standardize antigen design, integrate biopsy validation, and pursue longitudinal studies. Success could enable precision diagnostics and tailored therapy, transforming care for children and adults with nephrotic syndrome.

Is it time for targeted therapies for Glomerular Diseases?

Concept Map: How I treat Glomerular Diseases in the Older patients

 

Based on CJASN article published in 2025

Women in Nephrology 2025 Meeting at Northwell Health

Please see the announcement below for a very special conference taking place September 13 and 14^th  2025. The WIN Leadership Conference is a 2-day interactive program that brings together speakers who are well-known international leaders in Nephrology to provide sessions related to finding and succeeding in leadership roles. It includes context, tools, and knowledge pertinent to careers in private practice, industry, and academia as well as the different career tracks within academia.

 

Please join us for a wonderful event!!!

Here is the eventbrite link:

https://www.eventbrite.com/e/2025-women-in-nephrology-leadership-conference-tickets-1384242549729?aff=oddtdtcreator