Concept Map: APOL1 Mediated Kidney Disease (AMKD)

 

Consult Rounds: the Heart Failure, hyponatremia and no clues on physical exam???-- Detective Nephron style

The Heart Failure That Left No Clues on Physical Exam

Patient: Severe heart failure

Exam: Shockingly normal
Question: Where did the signs go?

CLUE #1: The Missing Congestion

• No crackles

• No JVD

• No edema

What may be happening?
Chronic HF adapts. Lymphatics drain. Veins stretch. Congestion hides.

CLUE #2: The Resting Alibi

• Looks fine in bed

• Symptoms only with exertion

What really is happening?
The exam interrogates patients at rest—CHF commits its crimes on exertion.

CLUE #3: Masked by Modern Therapy

• Diuretics

• ARNI / MRA

• SGLT2 inhibitors

What is possible?
Congestion is controlled. The disease is not.

CLUE #4: The Low-Output Plot Twist

• Poor perfusion

• Fatigue, weakness

• No obvious volume overload

This is Low-output HF leaves few visible footprints.

CLUE #5: Body Habitus Interference

• Obesity

• Thick chest wall

Strange: Classic signs are present—but physically undetectable.

What a nephrologist can do to get FORENSIC EVIDENCE 

What solves the case when the exam fails:

• Echocardiography -- looking also at IVC

• BNP / NT-proBNP

• Lung ultrasound (B-lines > crackles)

• Hemodynamics when needed ( RHC)

Severe heart failure with a silent physical exam

Verdict: The bedside exam detects overt congestion, not chronic compensation or low-output physiology. Use POCUS wisely!

HSCT -TA-TMA, the Kidney, and Complement-Targeted Therapies: Where We Are Now

Hematopoietic Stem Cell Transplant-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation characterized by endothelial injury, microvascular thrombosis, and multiorgan dysfunction. The kidney is the most commonly and severely affected organ, with patients frequently developing acute kidney injury, proteinuria, hypertension, and long-term CKD. Renal involvement strongly predicts poor survival.

A figure from a recent review summarizes the challenges we have to diagnose TA-TMA and the limited treatment options of steroids, rituximab, and maybe eculizumab in certain cases.

Mounting evidence implicates complement dysregulation, particularly beyond the terminal C5 pathway, in TA-TMA pathogenesis. The strongest clinical data to date support narsoplimab, a monoclonal antibody targeting MASP-2 in the lectin pathway. Across multiple expanded-access and real-world case series—including the largest global cohort—narsoplimab demonstrated markedly improved 1-year survival in both adults and children, many with baseline renal dysfunction. Outcomes were best when used early, and safety signals were acceptable. These data culminated in FDA approval in December 2025 for TA-TMA in adults and children ≥2 years.

Beyond MASP-2 inhibition, upstream complement blockade is emerging. Iptacopan (factor B inhibitor) has been reported in small adult case series with improvement in hematologic markers and reduction in proteinuria, supporting a role for alternative pathway inhibition. Pegcetacoplan (C3 inhibitor) has been described in pediatric off-label cases and is under prospective investigation, reflecting interest in broader complement control for refractory disease.

Together, these studies suggest that earlier, upstream complement inhibition may provide better protection for the renal microvasculature and improve outcomes in TA-TMA compared with C5-only strategies.

HTN and TMA- Topic Discussion

Malignant hypertension with AKI or AKD is a life-threatening emergency that demands rapid blood-pressure control and carries a high risk of permanent kidney damage. When thrombotic microangiopathy (TMA) is present, diagnostic challenges intensify. Although complement-mediated TMA frequently presents with severe hypertension, malignant hypertension itself can cause TMA-like vascular injury. This has been a point of debate for many years. Does the TMA cause HTN or is HTN a cause of TMA as well? 

Early evaluation must therefore exclude secondary hypertension and secondary TMAs, which require etiology-specific treatment. Because a definitive distinction between essential hypertension and complement-mediated TMA relies on genetic testing that takes weeks, clinicians must use clinical and histologic clues to guide early complement-blocker therapy. Significant gaps remain in understanding pathogenesis, diagnosis, and treatment. A recent paper in KI really takes this to a better understanding. 

Some key messages from the review article

1. Malignant hypertension can directly cause a true TMA.
Severely elevated blood pressure can injure small vessels, leading to endothelial damage, platelet consumption, hemolysis, and classic TMA findings. This is not simply “secondary hemolysis”—it is a bona fide microangiopathic process.
2. Distinguishing hypertensive TMA from other TMAs is critical.
Hypertensive TMA can mimic HUS/TTP and complement-mediated TMA. Misdiagnosis can delay the correct therapy. The clinical context (markedly high BP, long-standing HTN, LVH, retinal changes) is key.
3. Treatment hinges on rapid but careful blood-pressure control.
The cornerstone is controlled BP reduction—typically in the ICU—with parenteral antihypertensives. This alone often reverses hematologic abnormalities and improves renal function.
4. ADAMTS13 and complement studies help guide management but should not slow treatment.
Work-up is important, especially when features are atypical or improvement is slower than expected. But initial management should start immediately based on clinical suspicion.
5. Kidney recovery varies widely—follow-up matters.
Some patients experience near-complete recovery; others progress to CKD or ESRD, especially when treatment is delayed. Long-term blood-pressure control is essential to prevent recurrence and preserve renal function.

     An important component is the heme component of TMA and it's presence in the systemic form of TMA. The figure( similar to the paper in KI) suggests that the complement-mediated TMA had most likely to have heme parameters of TMA as well followed by drug induced TMA and systemic diseases.  HTN is not that common. 

 

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