Professor, Lab Medicine & Pathology, Mayo Clinic, MN. Use Twitter to teach, clinical info changed to protect confidentiality. Love dogs. Views are my own.
Finally. We figured out the dense deposits in dense deposit disease (DDD).
The answer is Apolipoprotein E.
You can stain for APOE & make the diagnosis of DDD in >80% cases. Without electron 🔬.
DDD was the reason I got into mass spectrometry 17 yrs ago.
Excited about discovering a new antigen in membranous nephropathy (MN): Semaphorin 3B (Sema3B). Sema3B is a unique antigen detected in mostly childhood MN. Lot of work plus great collaboration. (1/3)
A comprehensive review on glomerulonephritis (GN). It’s a huge topic and it took a while, but we enjoyed writing this one. We tried to cover all of GN. An up to date reference for residents and fellows.
@MayoClinicNeph
@MayoClinicPath
@MayoClinicGIM
Never seen this: ? Whipple’s disease in the kidney.
Patchy accumulation of aggregates of PAS-positive rods in Bowman’s space, few capillary loops, interstitium & tubules.
Initially thought of crystal storing histiocytosis but IF negative for Ig. EM showed bacteria in tubules.
1/6. Here is my approach to work up of the antigens in membranous nephropathy (MN). It’s not perfect.
@NephRodby
@GlassockJ
Start with the common (~60 %) group: This includes:
PLA2R, followed by
NELL1.
I had no idea at first, then it suddenly hit me.
1. Normal glomeruli,no FSGS
2. Tubules filled with large granules
3. IF negative=not light chain tubulopathy
Chromogranin +++ in tubules
Dx: Neuroendocrine tumor-associated tubulopathy
65-yr, diabetes, HTN, pancreas mass, ⬆️ Cr
Thrombotic microangiopathy (TMA) day: 2 types.
1.Vascular TMA: Arteries with fibrin thrombi & onion skinning of media. 45-yr old with AKI, HTN & ? scleroderma
2.Glomerular TMA: double contours (arrow), mesangiolysis and lobular tufts. 50-yr old treated with Gemcitabine for Ca
Something other than election results 😀! I had an IgA day. C3 is helpful in determining etiology. In IgA nephropathy (upper row) C3 varies 1-3+. In IgA-dominant infection related GN, C3 is 3+ (lower row). Think infection-related GN when you see super bright C3 in setting of IgA.
So IgA on kidney bx:
1. IgA nephropathy
2. IgA vasculitis/HSP
3. IgA-dominant infection related GN (often staphylococcus)
Often exudative on LM, IgA= GBM + mesangial, bright C3>IgA, usually humps on EM
Most imp: h/o infection, often diabetic
4. IgA in lupus along with other Ig
I want to take this opportunity to respond and explain MPGN.
The basic premise is that an underlying etiology can determined in most cases of adult MPGN.
Idiopathic MPGN I, II, III is poor terminology for a disease entity where an etiology can be determined. 1/12
Our Mayo Clinic Membranous Nephropathy Consensus Report is finally out.
A year in the making.
The manuscript brings together the recent advances in MN.
I am very thankful to all my collaborators.
@MayoClinicNeph
@MayoClinic
@MayoClinicPath
NELL-1 associated MN is out! We used mass spec, IHC & confocal microscopy to identify a novel antigen NELL-1 in primary MN. Serum antibodies to NELL-1 were also detected. NELL-1 appears to be the 2nd most common MN.
NELL1. Finally, we can order NELL1 IHC stain on our kidney biopsies for membranous nephropathy. Also, test is available through Mayo Clinic Laboratories. In my view, NELL1 is the second most common antigen after PLA2R.
Let’s talk membranous nephropathy:
Autoimmune (IgG) response to antigen (Ag) forming IgG-Ag immune complexes along subepithelial region of glomerular base membranes (GBM), along with massive podocyte injury with ensuing proteinuria. 1/10
Congratulations Aishwarya on your graduation from the Pathology Residency Program. Aishwarya was a coauthor with me on at least 15 manuscripts. She is one of the hardest working residents I have known. We will miss you. Good luck with the hematopathology fellowship.
@aravindranmd
Severe TMA (likely aHUS) triggered by COVID. Case today. Arteries=intimal thickening with mucoid material, schistocytes, obliteration of lumen (thin arrow) and thrombi (thick arrow). Normal ADAMTS13. Young man with ARF, hypertension, low platelets, schistocytes & COVID infection.
COVID-associated seronegative lupus nephritis (LN)! Immune-complex GN, with features of diffuse LN. Except negative lupus serology& no history of lupus. Bx shows MPGN on LM, full house IF & numerous capillary wall deposits on EM. Young woman with COVID, hematuria, proteinuria 10g
So many diagnoses, ONE trigger: recent COVID infection. Difficult case.
1. Collapsing focal segmental glomerulosclerosis (FSGS)
2. Thrombotic microangiopathy (TMA)
3. IgA nephropathy, IF 3+ IgA (not shown)
29-year old, acute on chronic kidney disease, recent COVID x 2, S Cr 7.5
Got a case of membranous nephropathy (MN) in a 2-yr old. Did the stain for Sema3B. And it was positive! I was happy to provide a more definitive diagnosis of Semaphorin 3B-associated MN! (Instead of just PLA2R-negative MN). IHC showing granular GBM staining using anti-Sema3B ab.
PCSK6 is the target 🎯antigen in NSAID-associated membranous nephropathy (MN).
Out in print today.
Another 🎯antigen of secondary MN identified.
You have to think of each new antigen as a unique Ag that is filling the antigens of secondary MN puzzle.
It was an honor to present Dr. Glassock with the 1st lectureship award in his name at the 32nd Mayo Nephrology Group Meeting at the ASN. He is a great inspiration, role model, mentor, colleague and friend. Thank you Dr. Glassock for your tremendous contributions to Nephrology.
Interstitial nephritis with numerous eosinophils. The cause= Atheroembolic disease. Pic shows an artery completely occluded with cholesterol emboli. Always look for atheroemboli when you see eosinophils (arrow). Back from teaching/vacation: interesting cases these last 2 days.
All patterns of FSGS in a single case!Perihilar, tip, NOS, collapsing. Goes to show that FSGS pattern is not really helpful in differentiating primary versus secondary FSGS. EM foot process effacement more helpful. 41-yr old with nephrotic syndrome (U protein 12 gm/day). Neg HIV.
Congratulations to my friend
@fervenzafernan1
for receiving the Mayo Clinic Distinguished Clinician Award at the 2023 annual staff meeting. Most deserving. Happy and proud.
Sometimes a simple stain can make a pathologist’s day. In this case, positive NELL1 in a case of membranous nephropathy today.
Dx: NELL1-associated MN.
79 yr-old smoker with 2 grams proteinuria. Cr 1.7
Will need malignancy work up, as NELL1-MN often associated with malignancy.
C3 glomerulonephritis (C3GN). Case yesterday. MPGN pattern of injury, bright C3, negative C4d (indicates alternative pathway activation), numerous capillary wall deposits. Previously, would be called MPGN III. C4d is useful. In 70% C3GN C4d is negative and confirms AP activation.
Happy and excited about finding EXT1/EXT2 as likely target antigens/biomarkers in secondary (autoimmune) membranous nephropathy; including class V lupus. >2 years of work. This will change secondary MN as PLA2R changed primary MN
#lupus
@MayoClinicPath
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IgG4-related disease (today): Interstitial nephritis with (key points to dx)-
1.Background of fibrosis
2.Numerous plasma cells (blk arr) & few eosinophils (white arr)
3.Plasma cells stain for IgG4 (>10/HPF).
Also did IgG:IgG4=Almost all IgG + cells were also + for IgG4. 1/2
Lupus vasculopathy: under recognized.
Large vessels with Ig deposits & no inflammation.
Bx: thick vessel walls with accumulation of IgG & C3. No arteritis.
Dx: 1) ATN 2) Lupus vaculopathy 3) Mesangial lupus nephritis (class II)
35 yr with lupus & rise in S Cr to 2.5 from 1.2.
Kidney biopsy showing interstitial nephritis with perivascular granulomas.
Dx: Granulomatous interstitial nephritis, consistent with Sarcoidosis.
No arteritis, therefore not granulomatous arteritis.
40-yr old man with AKI, increased serum calcium, lymphadenopathy.
Case today
Nuances of Membranous antigen staining:
1. PLA2R: granular staining along GBM
2. THSD7A: lumpy-discrete, scattered deposits along GBM (linear staining=negative)
3. EXT: granular staining along GBM, can be intense
4. NELL1: granular, can be segmental,sometimes appears linear. 1/2
Be careful in over calling C3GN: 3 consults I saw that are not C3GN.1) Chronic TMA: can entrap C3 (and IgM). Entrapped material is hyaline appearing;2) Proliferative GN with monoclonal Ig deposits- the MIg may be v subtle on IF;3) New monoclonal Ig drugs (mabs) deposit & cause GN
Post-COVID Acute Thrombotic Microangiopathy (TMA).
As severe a TMA I have seen.
Thrombi (arrows) restricted to mostly glomerular capillaries and arterioles.
Arterioles feeding glomerulus clogged with thrombi (arrow).
40-yr old with COVID-infection 2 weeks ago, NSAID-use & AKI
ALL: Never quite seen anything like this in a COVID patient and AKI. I was expecting just ATN. Instead saw a sea of blue cells separating tubules. Work-up revealed acute lymphoblastic lymphoma/leukemia (ALL). 35-yr old previously healthy man with recent history of COVID pneumonia
Different flavors of IgA: 3 cases this week. 1) IgA nephropathy in the setting of Crohn’s disease, 2) IgA dominant GN- infection (Staph) related, 3) Henoch Schonlein pupura. All show bright IgA on IF and many mesangial deposits on EM. Clinical-pathological correlation is key.
Excited! Earlier this year we discovered the putative antigen EXT1 EXT2 in membranous nephropathy (MN) in the setting of autoimmune diseases-see link. We have now discovered the next most common antigen in MN after PLA2R; paper should be online next week.
Complete set of definitions and examples of almost all glomerular lesions seen on kidney biopsy. It is a consensus document and a great guide to understanding the lesions as well. I would bookmark this manuscript as a reference.
Immunotactoid glomerulopathy: almost missed it in a diabetic patient. LM=PAS+ nodules, routine IF was negative but EM (B-D) showed few subendothelial deposits with tubular substructure. Pronase was very helpful=negative kappa (E) and positive lambda(F). Turned out IFE + = lambda.
IgG4-related disease: all the findings! Fibrosing interstitial nephritis (storiform pattern), lymphoplasmacytic infiltrates with few eosinophils, plasma cells strongly positive for IgG4. There was a high IgG4:IgG ratio (not shown). Differential diagnosis includes ANCA-vasculitis.
I am always amazed by this simple finding in glomerulonephritis: Red blood cells in a tubule. This is in a patient with IgA nephropathy. Electron microscopy showing numerous degenerated RBCs, that in all likelihood are causing a lot of tubular injury.
Great teaching case: Cryoglobunemic GN, type 1.
LM: membranoproliferative GN pattern, with intraluminal and capillary wall deposits (trichrome and PAS + silver-)
IF: IgG lambda, kappa -
EM: intraluminal and subendothelial deposits with tubular substructure
50-yr old with CLL
Just realized that 4 manuscripts I wrote came out in print this week. Happy Friday.
1. NDNF is the target antigen in Syphilis-MN.
2. Almost there, putative antigens in MN.
3. Many faces of NELL1-MN. (Title borrowed from GOT).
4. C3G-aHUS crossover. 1/2.
Lupus, class IV: no explanation! Massive Ig deposits with wire loops (thin arrows) in upper half of glomerulus, yet devoid of cells. Bottom half- less deposits but a proliferative GN (thick arrows). Perhaps Ig deposits in upper half too massive to handle for inflammatory cells.
FSGS. Up to date review defining-1. Primary/permeability factor FSGS, 2. Genetic FSGS, 3. Secondary FSGS, including maladaptive, drug-induced, viral-induced, and FSGS-associated with other glomerular diseases. Clinical & pathology correlation is key.
Good learning case.
Kidney biopsy findings in Sickle cell disease.
Kidney bx:
1. Chronic thrombotic microangiopathy
2. Secondary FSGS
3. RBCs sickling in glomerular capillaries
4. Tubules filled with iron pigment
54-yr old with sickle cell disease, proteinuria, rise in S. Cr
Few take home messages on new Ag: 1)EXT1/EXT2: autoimmune dis, good prognosis, 2)NELL1: Mostly primary, 2nd common Ag, segmental staining, also malignancy asso- 3)Sema3B: childhood Ag, 4)PCDH7: older pts, non-complement activating, milder 5)NCAM1-primary & autoimmune dis 6) HTRA1
An absolute honor for me to talk on membranous nephropathy with 2 of the most revered nephrologists and membranous nephropathy ‘gurus’.
I could not have dreamt of speaking in front them as moderators of my talk.
I am truly humbled and still in awe.
🙏 Sardinia for inviting me
Phospholipidosis Glomerulopathy. Very interesting finding on EM. Podocytes filled with multi-lamellated whorls of lysosomal vacuoles (arrows). LM findings were v subtle, easily missed. Digging around-turns out the patient was on a lipophilic antifungal drug for many months.1/2
The 5 most common questions I get from nephrologists
• What is the diagnosis?
• How active is the lesion?
• Is there ATN?
• How much scarring is present?
• Is it treatable or too late to treat? These should be answered in the kidney biopsy diagnosis
This is how I would estimate % crescents (or other lesions). Calculation is based on total glomeruli. I will give examples:
1. If you have 10 glomeruli of which 9 are globally sclerosed & the single remaining glomerulus shows a crescent, to me that is not 100% crescentic GN. 1/4
Crescent: have not seen one this big!A cellular crescent (arrows) weaving its way from the Bowman’s space all the way into the proximal tubule...like a jug handle. Same glomerulus showing necrosis (arrowhead). 50-yr old diabetic with acute renal failure.
At first glance: simple ATN. Look closely~you see yellow-brown pigment in epithelial cells. IHC for hemoglobin was + & Iron stain was stunning-most cells were loaded. Diagnosis: ATN, secondary to Hemolysis. 45-yr old, liver transplant & acute renal failure. Turns out pt has PNH.
Myeloma kidney: Casts with geometric shapes filling tubules everywhere.
Sometimes it’s hard to find one typical myeloma cast but in this case they are everywhere.
Kappa light chain on IF, lambda negative.
67-yr lady with AKI. S Cr 6.5, up from 0.8. Monoclonal work up pending.
BK nephropathy teaching point. Protocol transplant biopsy showing inflammation (red arrows) in cortex. ISH showed BK (black arrows) in scattered tubular epithelial cells-not in cortex but in medulla, mostly where there was no inflammation. Always look at medulla for BK infection.
C
#35
.FSGS in 45 yr old with recent onset frank nephrotic syn(NS). The nephrologist asked me:primary or secondary? Simple rule of thumb in adults (in absence of diabetes): NS=Primary FSGS; slowly progressive proteinuria (nephrotic range, but not NS)=secondary FSGS. EM very helpful
Landmark study on treatment of severe ANCA-GN: rituximab vs cyclophosphamide, and role of plasmapheresis. I scored >250 ANCA-GN biopsies. Happy to be part of the study.
@fervenzafernan1
All the classic features of thrombotic microangiopathy in Scleroderma. A) Glomeruli with mesangiolysis, B) Thrombi in small arteries, C) Mucoid material in thickened intima, D) Onion skinning of media,+ischemic glomerulus next to the artery. 50-yr old with ARF, scleroderma & HTN.
Hyperacute (antibody-mediated) rejection: severe peritubular capillaritis & glomerulitis (arrows), glomerular thrombi (thick arrow), ATN.
C4d was negative: too early to turn +
Don’t see this anymore.
Rush case last night. 60-yr old, kidney transplant 2 days. Pain abdomen. DSA+
1. Focal necrotizing lupus arteritis.
Plus severe lupus vasculopathy.
Can be missed and is unfortunately not part of the lupus classification.
2. Glomeruli showed mesangial lupus nephritis, class II.
40-yr old woman with lupus & rise in serum creatinine,+ lupus anticoagulant.
A red cell crescent! Red cell cap over the glomerular tufts! Not sure what to call it😃.
The entire Bowman’s space is filled with RBCs. I am always amazed by how RBCs get through the intact capillaries.
Doing few EMs over the weekend. Tol blue section.
30-yr woman with lupus.
Two different lesions in one glomerulus.
Top half: thickened GBM, no inflammation
Bottom half: endocapillary hypercellularity, segmental
Dx: 1) Focal lupus nephritis, class III; 2) Membranous lupus nephritis, class V
29 yr lupus pt with 8 gms proteinuria, Cr 0.9, albumin 1.8
Just out. The story & key features of new MN antigens:
EXT: autoimmune disease (lupus)-associated, good prognosis; NELL1: primary & malignancy-associated; Sema3B: pediatric antigen; PCDH7: primary, minimal complement, remission with conservative treatment.
Everything you want to see in EM of membranous nephropathy (MN)
Subepithelial deposits (black), reabsorbed lucent deposits (white), basement membrane material/spikes between deposits (*), podocyte injury/effacement (yellow).
Most amazing thing is the still intact GBM (red) 1/3
Tubule crammed with RBCs! Electron microscopy of a RBC cast that has packed and distended a tubule in a patient with myeloperoxidase (MPO)-glomerulonephritis. Case from today.
Another weekend transplant case: Diagnosis is easy, but cause unknown.
Oxalate nephropathy, tubules filled with bluish birefringent geometric crystals.
Not sure where the crystals are coming from.
55-year old, 3-post transplant. On dialysis. Primary disease hypertensive ESKD.
Teaching casts in myeloma kidney:
Light chain casts (black arrows) are PAS negative, have geometric shapes, fractured appearance (c/w myeloma).
Tamm Horsfall protein casts (white arrows) are PAS positive, have a flocculent layered appearance (c/w scarring & obstruction). 1/2
A case of Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg Strauss Syndrome. Eosinophilic interstitial nephritis (A,B) + necrotizing (C,arrow) crescentic glomerulonephritis. 57-year old man with acute renal failure, eosinophilia and positive pANCA titers.
Glomeruli exploding with rupture of Bowmans capsule and a mushroom cloud of epithelial cells streaming out (B,C). The epithelial cells (mushroom cloud) appear to form granulomas covering/adjacent to glomeruli (arrows). Case of severe crescentic anti-GBM glomerulonephritis today.
Collapsing glomerulopathy (CG) 🆚 crescent can be difficult. This is CG. CG pointers=protein droplets (thin arrows) in podocytes & tubules, podocytes (thick arrows) look epithelial 🆚 spindle, + NO fibrinoid necrosis. Cystic dilatation tubules. Patient with HIVAN, h/o drug abuse.
Nothing else can look like this: Anti-GBM glomerulonephritis. All you need is good immunofluorescence studies= that show linear (A) IgG, (C) kappa & (D) lambda along capillary walls. Plus glomerulus filled with (B) fibrin. 75-yr old with AKI, wkend rush bx. Don’t even need LM/EM
Anticoagulant-associated hematuria.
It’s simple but easy to miss.
RBC’s in tubules.
RBC’s in glomeruli-in urinary space in between tufts & in Bowmans space.
No RBC casts, RBC’s look fresh (arrows).
60 yr-old with hematuria, MGUS, DVTs & CKD. Rule out MGRS. On anticoagulants.
Very pleased- this is a niche and specific antigen.
Hematopoietic Stem Cell Transplant-Membranous Nephropathy is Associated with Protocadherin FAT1 1/2
Cocaine-associated thrombotic microangiopathy. Severe endothelial and intimal injury with mucoid material accumulation (black arrows) and almost complete occlusion of vascular lumen (red arrow).
TMA with severe mesangiolysis. The mesangium reacts to ischemic injury by loosening and breaking up. Numerous capillary microaneurysms form containing loose foamy matrix material. A case of Avastin (anti-VEGF)-induced TMA. 40-yr old woman with ovarian cancer and renal failure.
Weekend case:
Necrotizing glomerulonephritis: Fibrinoid necrosis (arrow) in only one free floating glomerulus, out of 25 glomeruli. Consistent with MPO/pANCA-GN
MPO/pANCA-GN can be notorious for very focal involvement.
65-yr old with diabetes and acute kidney injury.
Semaphorin 3B-associated membranous nephropathy (MN).
Not just in children but young adults as well
Immunohistochemistry (IHC) showing glomerular capillary wall staining for SEMA3B in MN.
Negative IHC for PLA2R, NELL1, THSD7A & EXT
33-yr woman with 13 g of proteinuria. Cr 0.5
2,8-dihydroxyadenine crystalline (DHA) nephropathy (yesterday): Rare but recognized it instantly.
The crystals are green-brown, superbly birefrigent, large but also tiny crystals all over: tubules, tubular cells & interstitium.
40 yr man with hypertension, diabetes, ⬆️ Cr. 1/2
Lipoprotein glomerulopathy. Got this rare entity this week. Can be confused with cryoglobulins/hyaline. Glomeruli filled with silver/ PAS negative material; MPGN pattern. EM= homogeneous material, may even resemble Ig deposits but can find varying sizes of lipid vacuoles;. IF=neg
High prevalence (62%) of collapsing glomerulopathy in COVID-19 in Mayo biopsy series. Although pts have nephrotic range proteinuria, foot process effacement is not diffuse + s albumin is normal in most, suggests CG in COVID is not a primary podocytopathy.
Membranous nephropathy, Exostosin positive.
I was not expecting this, but was glad to have an answer with respect to identifying the underlying antigen.
PLA2R & NELL1 negative.
Uncommon in a 65-yr old woman with nephrotic syndrome. Positive ANA, other serologies negative.
1/2 Really a simple concept: Membranous Nephropathy is just another pattern of injury resulting from different diseases.Should not lump them all into single entity of MN. I enjoyed writing this during my 4 hour transit break in Chicago on return from India
Atheroemboli. Subtle but important clue in panel A-Interstitial fibrosis (IF) somewhat diffuse and more than tubular atrophy (TA). Tubules appear OK in a background of IF. Thus, TA does not match up with IF. Always look for atheroemboli (arrows). Invariably find them. Bx today.
How focal can Sarcoidosis get!! Six long cores and a single well demarcated GRANULOMA (arrow) with numerous giant cells. Almost no interstitial inflammation in other cores, just mild focal global glomerulosclerosis and IFTA. 40-yr old with hypertension, CKD and h/o sarcoidosis.