Hollander Rounds: A Clinical Problem-Solving Case

All right, I'm ready to get us started today. Um, we've got a, um, the next in our wonderful series, clinical problem solving. Um, which is named after, um, Dr. Harry Hollander, who I'm pleased to say is in the audience today, um, the former IM program director here and an infectious disease, um, and internal medicine doctor extraordinaire. Um, so we're very excited to welcome Dr. Chris Carlos um to the podium um slash the Stage today. Um Dr. Carlos is an associate professor of nephrology here at UCSF Health. Um and he is core faculty at the UCSF

glomeular disease center um where he works in a team-based setting to treat complex immune mediated kidney disease. Um he does research in rare glomemeular disease and is also the um fellowship uh program director for nefrology. Thank you so much. >> Welcome. >> I appreciate it. And thank you so much for uh inviting me. It is a huge honor and it's so great to see Harry. Uh it's actually coming up on uh 10 years I've realized now since graduating from this uh uh residency program. And uh this has obviously shaped a lot of how I uh

live my life and kind of the the life that I lead now today. And it's uh just talking to some younger house staff about the many pivots that happen along the career pathway. very excited to be here today. So, thank you. >> Yeah, thank you. Thanks for being game. All right. So, um some ground rules which are the same for every CPS, but just as a reminder here. So, um Dr. Carlos does not know the diagnosis in the case, but the diagnosis is not necessarily the point here. The the goal is to really walk through

um the twists and turns of this case um and learn from Dr. Carlos's clinical reasoning and clinical knowledge. Um, we do encourage Active audience engagement. So, if you have a question or a comment, raise your hand. Um, and I can bring the handheld mic to you. Um, and the main goal is to have fun. Um, so any any last words before we get started? >> I don't know. Hopefully this is uh not a hyponetriia case, but but we'll see. >> Well, we never see this person, so I'm sure it's not. >> All right. So, let's

get started with the history of present illness. So, we Have a 57year-old man. He has a history of hemorrhagic stroke back in 2016 with residual right-sided weakness, prior right leg DVT, not on anti-coagulation and hypertension who comes in with weakness and fatigue. And just to say we'll have stop points throughout um their blue slides um just to have various pauses. So a little bit more about this uh presentation. So this is August 2025. He's coming into the emergency department via urgent care After his legs, as he described it, gave out at home, resulting in a

fall. Um, he noted that over the last couple of weeks, he'd had both centralized leg weakness as well as generalized weakness. He denied any dizziness, consciousness, chest pain, palpitations preceding these falls. He really tied it to the weakness in his legs. Um, and he had also noted dampness in his pants and underwear over the last few weeks, and that required changing his clothes Several times per day. In terms of his functional decline over the last couple of weeks to months, back in June, he was really able to perform all of his activities of daily living

on his own, but uh over the subsequent month or two went to essentially being bedbound. um and notably he'd been um disengaged with the medical system for several years since about 2020 or so. Okay. So, we just have some very sort of general information and so likely a very Broad differential, but curious um what you might be thinking in terms of somebody coming in with um new weakness who's been maybe lost to medical care for a while. >> Well, I think the the differential is quite broad. I think that in general um in our I

think just failure to thrive type of picture although this patient's in his 50s it sounds like um it wouldn't typically fit with uh kind of this more frailty picture that is more slow onset But over the last five weeks it sounds like seems to be somewhat of a pretty rapid uh decline. I think more global kind of systemic illnesses of infection could kind of present as just generalized fatigue and weakness. I'd be worried a little bit about any sort of new neurological symptom uh that has uh kind of in his demographic that we should be

worried about, but probably just prompting a more generalized kind of workup at this point. >> Great. Yeah, didn't give you too much to go on so far. So, >> very general medicine leadin, but yes. >> Thank you. So when this patient's in the emergency department, the team is looking back at his at the medical records that we have um and notable were um some lab values in 2016 where he was noted to have a lucopenia on just routine outpatient labs. Um didn't really have contact with the health care system again until 2020 When he was

noted by his primary care doctor again on sort of routine screening labs. He was feeling fine. He's found to have a lucopenia with white blood cell count in the ones to twos. And at that point he underwent um some additional testing where he was testing for tested for HIV. He had an anti-uclear antibbody sent. He had rheumatoid factor sent and those were all negative. [gasps] The plan was for serial CBC's um and perhaps more workup But um again patient um was not um seen by the medical system again until December 2024. So about 8 months

before the emergency department visit that we are talking about in this case. So he came in around Christmas time for um leg and foot pain that was interfering with his ability to walk. In the ED he was found to have leg weakness and edema um as well as some uh pretty striking lympadnopathy. Um on examination he was found now to Not only have lucopenia but to actually have panzyopenia with hemoglobin in of around 10 platelets of 101 and white blood cell around his previous baseline of 2.3 and he had very elevated um inflammatory markers. The

ED team recommended he be admitted for further workup with imaging and labs. Um the patient um decided um to not do that and um directed his discharge home at that time um without patient neurology and hematology Referrals and unfortunately he did not um he was not able to follow up um with those providers. his past medical history. Um, most of which was in the oneliner. He had hypertension. He had a right leg DVT. He was not on anti-coagulation when he came to the emergency room in August. He'd had a hemorrhagic stroke in 2016 and had

residual right arm and leg weakness. Didn't take any medications. Did not use tobacco, drugs, or alcohol. Um, he was Had been unemployed since about the 1990s. um lived with his mother. So was housed and had traveled extensively um throughout the Philippines as a child. Review of systems was notable for again malaise, fatigue, falls, some constipation. Um he denied any weight loss, any fevers, chills, abdominal pain, diarrhea, dizziness, headache, lightadedness, and dyseria. And I promise we'll take a break pretty soon. Uh just giving you this, believe It or not, this is still just the very first

pass of the information that was collected on this patient. So um he his labs um his vital signs were significant for mild hypertension to systolic of 159. He was sitting well on ambient air. He was not tacocartic and he was aphibbrile. He appeared ill and was keectic. He had dry mucous membranes and was noted to have a tongue apis ulcer. Cardiopulmonary and abdominal exams were Normal. He was noted to have anarcha and neurologically he was alert and fully oriented. He followed commands. However, he was noted to have decreased strength in the right arm and leg

which was slightly worse he said than his baseline despite the prior stroke. He did not have any um saddle anesthesia. And then he was found on skin exam to have a sacral wound with purilin output up upon palpation. It didn't seem like that probed to bone and there was no Pain or crepitus over that. So moving on to labs for him. Um a lot of red values here but we can see that he has this continued lucopenia to three. He's anemic with a hemoglobin of of about 8. And his thrombocytoenia has resolved. It's 414 now

is his platelet count. LDH is high at 358. Vitamin D 25 hydroxy is low at 16. Albuan is very low at 1.5. Your analysis, >> hey, >> showed 300 milligrams per deciliter of Protein, 5 to 10 whites, 3 to 10 RBCs, and then his urine protein creatinine ratio was almost four milligrams per gram. >> Albumin to creatinine ratio was 782. His INR was slightly up at 1.3. Inflammatory markers were high. Serum iron and serum transfer were low. So, I'll I will go back to the lab slide so we can have it up, but wondering how

the labs that we got might shape the differential for this patient's Presentation. [clears throat] >> Thank you for uh all that information. I think that the most striking thing of the presentation obviously from a renal standpoint is um the evidence of the edema that has swollen or his swelling pattern and kind of the the time course is something that in his history that I'm obviously triggered to queue in on and try and understand and that in combination with the high degree of Proteinura uh at 3.9 mill 3.9 grams per gram kind of put that in

that classic nefrotic range proteinuria And that if we see the serum albumin is also low at 1.5. So what we're here at least from a kidney perspective trying to understand is that there is at least some signal here of a loss of protein that is exceeding the liver's ability to synthesize albamin. And so what you're doing is just losing a tremendous amount of protein usually all at once. And so I Think that that if we're trying to kind of understand uh or paint kind of a picture or like a syndrome on this, I think we're

all kind of clinically thinking about a nefertic syndrome. And when we think about a nephroic syndrome, I I want to kind of impress upon you that the the classic kind of lesion in the kidney that typifies a nefertic syndrome is really the ptoy. And the ptoyite is there as this kind of structural entity in the cell that kind Of maintains the the structure and then um helps keep all of the healthy proteins in. And then when there are diseases that interrupt or kind of ease what we call or injure the ptoite uh you can lead

to this kind of tremendous amount of protein loss and specifically albammen loss. And so the thing that is you know interesting here is that this is nefertic syndrome. But what I want to also kind of point out is that the I'm glad that you gave me like a Fractionated amount of protein because this is atypical the traditionally some many nefertic syndromes and when you look at how much protein is in the urine the predominant protein that's in the urine should be really albamin and albammen should maybe take up about 70 to 80% of the total

proteinura. So this is something that I think when you're ordering labs, we might ask you to send both a UPCR and a UACR because what we're trying to figure out is it's one Thing to kind of quantify that the total protein amount is too much that should be there, but what are the actual proteins that are there? So that's number one that's already I'm starting to think a little bit about my differential about what causes quite a bit of a protein gap in the urine. But then thinking kind of bigger picture I think the classic

thing that we think about with nefertic syndrome are generally like ptocytopathies in and of Themselves isolated ptoy injury but is this something of a more of a systemic is there something else that's happening in the rest of the body and so whereas I think that normally we're taught to think about ptocytopathies of minimal change disease fsgs and membranes nephropathy which are injuries specific to the ptoite that you don't necessarily see extra renal manifestations or problems in this patient where we're seeing some Signal of some neuropathy perhaps of some pain and and damage to nerves where

you're some um there's a history of chronic inflammation with an elevated CRP and ESR and you're seeing this large protein gap of non-alin proteinuria um I'd be maybe more concerned of something of like an amaloid picture um and amaloid takes two different flavors you can have an AL amaloid which is predominantly of kind of malignancy picture of you know plasma cell disgraia Versus an AA amaloid which is more which we see sometimes in our patients um at the general hospital that present with a history of chronic inflammation and chronic skin infections that have a high

degree of um [clears throat] a amaloid deposition. So I think that that if I could kind of as an early marker the thing that bothers me here is is a little bit of the UPCR and UACR discrepancy. >> What are you expecting to see? like what Is the typical you're saying discrepancy what's kind of the baseline that you're looking at that would not be atypical >> so to to go into because I think that we we have discussions on the phone call about kind of okay this meets our definition of nefertic range but is it

truly nefertic syndrome and nefertic syndrome is right where you lose the ptoytes and they kind of a face and what I want to say is that the albamin in the urine is is a protein that's very Specific to the glomemeilus versus when you see a non-albomen proteinuria, we're worried about tubular proteinuria or kind of spilling out a bunch of other proteins that are there. So if this were kind of an FSGS picture or a memorous nephropathy picture, um I would probably see a much more severe form of UPCR of on the order of like eight

grams, nine grams in association with this serum albamin that's very low. These are disorders that kind of uh Progress over a period of weeks and months. Um and I would see that the UACR is probably like I said kind of a much higher baseline. Now I want to maintain like a broad differential for like the ideology of a hypoalenemia. there's nutritional causes of hypoimanmia and in this person who might not have been eating very well or it's going to be a marker more of inflammation of the hypoamineemia and have nothing to do with the degree

of albaman loss and Nothing uh associated with the nephro that could be kind of like a little bit of a red herring as well. >> Is it weird that his creatinine is normal? >> That's a good question. So um in a purely uh ptoite problem you really should not have impaired GFR. Um we talk a lot about or we try to talk to our fellows a little bit about the triad of proinura hemuria and eGFR. And in that kind of Vin diagram that I like to kind of put on the board where are we in

kind of in this kind of space. um if the disorder is purely of the pto site you really should not have hematuria nor a loss of efr now there's kind of overlap with a lot of things heavy proteinuria could also cause tubular damage and tubular injury in the form of ATN so if there's concominant ptoyite injury and ATN you might have an eGFR decline but really um it's uh not at all surprising perhaps That the eGFR it might actually be helpful that things like FSGS which is more of a chronic sclerotic like chronic sclerosing picture

that's associated with more CKD um is not here um and is lower on my differential um you know with the neuropathy and a 55year-old you're worried about other kind of multiorgan causes of proteinuria things like diabetes and diabetic neuropathy but in this case um right like with hypertension that's something that's Always on our differential for a lot of people um but the fact that it's not chronic kidney dise Please tell me that maybe this injury is a little bit more um recent than it is something that's chronic from chronic sclerosis and and CKD. >> Great.

And sort of last question about this slide, the vitamin D, one of them being low, the 25 hydroxy um is that related in any way to the proteinura in your mind? I remember the Kidneys um help um create an active form of vitamin D. I'm going way back to step one now. Um, but does that flag in your mind? Do you think that's just your typical vitamin D deficiency from not enough intake in sun? >> Yeah. And I think that the discrepancy here where you know you're you're coming from the stored vitamin D level to

the activated vitamin D and the activated vitamin D is a little bit more active. You certainly haven't given me any um kind of dvillent medic or divalent lab data to say that if there's any sort of hypercalcemia for example but if there was kind of a discrepant um 25 hydroxy vitamin D to the 125 in the setting of hypercalcemia that would trigger me to kind of think of more of sarcoid pictures but traditionally sarcoidosis and kind of more granulominous diseases are interstitial and uh you know deposition and interstitial of the Stareyed kind of pattern of

injury is more in is a tubular interstitial chronic disease that would manifest as a lower EGFR and not necessarily an injury to the actual glamorous. So I don't know how to I don't know how to interpret that. That could just be a nutritional deficiency. >> Sure. And sounds like I didn't give you enough info to really Oh, >> it's okay. >> Um but that's helpful. Thank you. Any Other comments about anything you see on this slide? And you know, I think that this is a hard year analysis to kind of say I, you know, we

talk a lot about is there actual hematia and there's a lot of reasons why we might be um led to believe that there is actual hematia, but we're what as a nephologist we're looking for is specifically glomeular hematia. And so is there actual evidence on a urinary sediment that um kind of change allow us to believe that the Morphology of the RBC's show that the glomeilus itself is bleeding that there's some sort of superimposed itis a glomein nephritis where the the kidneys themselves are bleeding. Do they have a dysmorphic appearance? Are they in red cell

casts? Um to me this is kind of a non-specific ur analysis that I would want to follow up with either another analysis or um perform a urinary settlement. Thanks. >> Great. Thank you. >> Yeah. Let me let me get you a mic real quick. >> When the patient presented to the ED 6 months before this presentation, he was noted to have generalized lympadnopathy. That was not commented on on the exam. Uh, was the exam not done or was the lymphatnopathy gone at this at this point? >> Yeah, based on what happens next in the case,

I suspect it's just not documented On the exam, but it likely was still there. >> Thinking about the product. So, it's it's hard for me because I'm I'm still at the what I'm trying to do with just this is that um I'm actually only trying to understand what is happening in the kidney because it's almost overwhelming to kind of broaden to understand kind of what could be happening extra that leads to the damage within the kidney. But, But you're right. I think taking a step back our traditional buckets of autoimmune problems, malignant problems, chronic infection

problems still hold that you know gen like development of lympadnopathy and something that is more lymphoma based. It's could absolutely manifest in all the different forms of injury in the kidney. So it's kind of there was a lot in the kind of HPI that pro all of it probably could lead to various forms of patterns of of kidney Injury and that it might help to kind of further subclassify the the pattern of kidney injury and then once we arrive at maybe a likely pathologic diagnosis then we can kind of rebroen and then go back to

the HPI to see what clinical clues might be happening in the rest of the body that is leading to that injury. Great. Thanks for the question. We have some imaging a radioraph of the chest which showed essentially bilateral plural eusions And then um I think because of the leg weakness he got a radioraph of the pelvis which essentially was negative acute showed some chronic mild joint space narrowing and and no evidence of osteo over where that ulcer was in the sacrum. CT chest can actually run through it here with the lung windows and then here

with more of the the soft tissue window but um grossly can see a fair amount of extra fluid there in the Uh plural thickening and the um plural eusions as well. Um and that's essentially what the read said. So moderate paricardial eusion and paricardial thickening um compatible with infectious or inflammatory paricarditis as well as bilateral plural eusions and then prominent medastininal and axillary lymph nodes as well. So we've got some cirrusitis going on as well. CT of the abdomen and pelvis Showed um the long and the short of it is that it showed evidence that

this chronic ulcer went into the um soft [clears throat] tissues but didn't involve the bone. So [gasps] maybe maybe less of a oneliner, maybe more of a fiveeliner, but um I guess you you touched on putting the context of the urine studies in particular on of the overall like clinical picture that he has and I'm so It may be sort of what you just said in response to Harry's question in terms of um looking at you know proteinur and how it might um might explain some of the other findings, but I'm curious if there's anything

that stands out in particular that you would really put up at the top of your summary of the patient so far? >> Yeah. So, I guess we have um a gentleman who's in his uh mid-50s who, you know, and thinking back to his past medical History. I think the only relevant thing that's there is that he's been out of care for quite some time and has come in with likely a a subacute kind of presentation described as as fatigue but also found to have lympadnopathy and um uh edema generalized edema and also this kind of

ulcer and is now found to have also uh well nephotic range proteinura hypoalmia um and uh normal renal function. And so I think sorry for the reverb. Uh I think Taking a very generalized picture, this is clearly something I'm worried about something systemic going on. And so in our generalized bucket of there's clearly signs of um active inflammation. The ESRCP is is kind of there and elevated. There's something um that you know we're worried about that still could be infectious in ideology. And I'm trying to think about things that link toward um a neuropathy picture

and ulcer as well as you know disruption of the Pto sites. And so you know on my differential under infection I would defer to kind of our infectious diseased colleagues but um I would want to send an RPR for things just like chronic undiagnosed syphilis can kind of present in some of these ways. And then going into the next uh picture of malignancy, we really do worry oftentimes about solid tumors and kind of could this gentleman just be presenting with some sort of um underlying lung disease or Underlying malignancy that we need to be worried

about, but also thinking about our plasma cell disrases of which uh amaloidosis I'm looking at that kind of protein gap of is there something that's a um a myoid pattern that's there and then kind of I think he had a lot of our autoimmune conditions ruled out earlier. he had like a negative ANA and a lot of our other processes and it doesn't quite fit a lot of the characteristics that we would think about that but that's also Just kind of broaden but um yeah it's still kind of broad that I would think about before

we send some kind of follow-up labs and spin the urine and kind of better understand and typify what's going on in the kidney to help I think that would be our role in the whole multi-disiplinary team is trying to figure out if there is kind of a a classic illness script even in the kidney that then I can help the team rebroad in to understand uh what's going On in the rest of the body. >> Great. Thank you. >> Next steps for what you might reach for. Um well I certainly would send um our generic

not to kind of have like a reflex of our usual chronic infections but we oftentimes send our um our HIV hepatitis B and C um and uh uh you know our syphilis our PR in this case would probably be relevant. um I'd be worried a little bit about the the malignancy workup and so I would send a pair of Protein screen as pep uh serum um immunofixation and and our free light chains and then I might also try to better understand on a 24-hour timed urine collection exactly how much is this um kind of uh

is the UPCR correlated very well to a 24-hour urine and also trying to figure out if that is a total protein as well as how much albamin is in it and then you can also send a urine protein electropheresis to kind of get at this that's bothering me This gap. I can tell like I want to understand what exactly is the protein that is that 3,900 and that'll give me a better indication of what's there. >> Great. Good to know the things that bother a nefologist. >> Um and then I wonder too I mean some

of the testing that was sent back in 2020 if you'd consider rescending that now that he's looking a little bit different um kidney-wise. Yeah, I mean I would get into these Discussions with like our rheatologists on whether or not lupus is still effectively ruled out. There's a lot of lupus um mimickers. Uh this seems to be kind of a systemic problem. Um and so I'd maybe think about obviously doing a repeat ANA. Uh for the autoimmune, which I kind of left because you can tell that I'm hedging more towards an infection and malignancy, but in

our autoimmune diseases, we're worried about ANA. We could send um in our kind of pulmonary Renal syndromes, we're worried about ankas. Um, but those would usually manifest more at loss of kidney function with a lower GFR. So, I'm not necessarily as concerned about that. Um, but I think that that's is that the the the labs of the four that you're kind of seeing if I would repeat? >> Yeah, he'd had an ANA and a rheumatoid factor and an HIV. >> Well, I'm certainly sending the HIV Again and the hepatitis corologies. Um, but I probably would

repeat the ANA just because why not at this point. >> Yeah, it's been almost six years, I guess. So, >> exactly. >> All right. Um, >> you sending compliments. Did I see that they were low somewhere? >> Um, there are many tests that are yet to come. >> Okay. [laughter and gasps] >> Um, but you are setting the stage for some of the workup. So he had all these fluid all this fluid on his lungs and he had a thora which showed um 345 total nucleated cells um an LDH of 249 um with the upper

limit of normal in the serum being 243 protein was three with a serum protein of 7 glucose was 43 pH was 7.48 48 there was no bacterial culture growth and cytology was benign. I know we're all thinking About lice criteria and I'll just summarize and say it's an exudative eusion all the math um but qualified um via multiple criteria there. So he had an exudative plural eusion and then he had really um not just the uh dynamic trio of infectious disease, hematology and room that we see so often in some of these patients with a

with a challenging diagnosis to make also neurology and nephrology. Um so infectious disease recommended a Pulmonary TB rule out hematology recommended a fat pad biopsy. You had mentioned amaloid previously. um a PET CT, bone marrow biopsy, SPEP, UU upupep, free light chains, cappa lambda light chains. Um neurology was considering an EMG, renal was um recommending a broader cerologic workup and considering a kidney biopsy. And then um rheumatology sort of agreed with nephrology and recommended similar things related to this concern for amaloid that You raised which I think the team was worried about as well based

on some of the factors that you mentioned. Um they um got a cardiac MRI that showed um fibrous stranding and paricardial inflammation um but really um was not actually suggestive of um cardiac amaloid. uh but noted that it was like a a limited study. Um and then the PET the patient had a PET CT which did not show a malignancy. Um the patient actually had a TTE before the cardiac MRI um Which led to the cardiac MRI but essentially had an EF of 50 to 55% and some LVH with some apical sparing that raised concern

for amaloid and a small paricardial eusion that was free flowing and there was no concern for tamponod physiology there. Some other results uh really rolled in over the next uh weeks uh days to weeks. So fatpad biopsy did not show amalloidosis. Um his SPEP and upp um was consistent With a polyclonal gamopathy. Um plural fluid flowcytometry was negative for lymphoma. Bone marrow biopsy was nothing to write home about with a mild plasma. Quant gold TB was indeterminate. and then he couldn't really produce sputum for pulmonary TV testing. And I'm I'm happy to also go back

to any of the studies to look at them too. >> Okay. >> But just wondering the uh differential That you had before with the buckets as you so nicely laid out for us. I was curious if any of those studies sort of had you put those higher or lower on your list. >> Well, I certainly think that amaloid is maybe a little bit lower after all of that. Although you know sometimes we can still have negative studies uh like a cerologic study for um a monoconal gmopathy that looks polyclonal on exam but then ends up

when you do a kidney Biopsy is all what we call this monoconal gopathy of renal significance. Um I am led to believe that you know I did forget about like tuberculosis and obviously with that uh vitamin D discrepancy and some sort of uh um you know we'd want to kind of still lean in a little bit on our infectious disease colleagues to see if there's any sort of other red flags with that history of his uh frequent trips to the Philippines in the past of just understanding um the Status of that. Could that explain a

lot of his um kind of fatigue and and kind of generalized weakness symptoms? So, in my generalized buckets, I'm still a little bit uh confused about what the renal pattern of injury is. And and because of that, pretty much, as I said before, everything all the buckets can kind of manifest. Um it hasn't really narrowed my differential significantly. Still, I'm still waiting for um kind of all of us to further clarify their their Injury a little bit more. >> Great. And then I suspect the testing that you want is similar to what you said. thinks

that he needs a kidney biopsy at some point. Um but as far as I can tell like the similar testing to other P corologies to come return as well. >> You do you do think he needs a kidney biopsy? >> I mean I think that in this in these diagnostic um kind of dilemmas there's Nothing that beats tissue to kind of further understand exactly what the pattern of injury is. And um as one of our like biopsy um faculty members, as long as they're I mean I forgot to see what the platelets were, but as

long as the risks are there for a kidney biopsy, it would probably help um understand exactly what's been um what's been going on uh with at least that organ. >> Yeah, perfect. Platelets were 414, so should be good. [gasps] So we have some more salient information here. So, the patient had a 24-hour urine protein which was 2 grams. Uh, an elevated serum IGG and IGG4. Um, had an ANA that um, we had talked about rescending um, which was positive at 1 to 1280, a diffuse pattern. Double stranded DNA was off the charts at 6,000. Compliments

you had asked about before. They were both low. Anti-Smith antibbody was 70.4 four and anti-IN R&P antibodies uh those were both elevated. Anti-phospholipid A2 receptor was negative. You can tell us what that means exactly in just a minute. >> Yeah. >> Um ACE level was normal to low. IL6 level was high compatible with inflammation. Anti-Pr3 was negative. AntiMO was negative. >> Yeah. Sit here for a little bit. Yeah. Maybe, you know, obviously in retrospect, was I anchoring too much on That prior negative ANA? And and to be fair, um there's a lot of things that

are lupus monikers or mimickers, I should say, that aren't exactly classic systemic lupus. Um, but I think at this point I'd be worried um, and I'm trying to channel Sharon Jung a little bit and Maria Delera about um, kind of also things that could present with uh, kind of atypical patterns of positivity of both um, and obviously trying to remember my Lecture of what these anti-smith and anti-RP antibodies signify. But certainly I think that the low compliments do suggest a little bit of a chronic inflammatory state. And as we know or as we know, you

know, a lot of chronic systemic inflammation that's more of a circulatory problem can then deposit as immune complexes within within the kidneys. The 24-hour urine protein now repeated and quantified as being 2 grams is a little bit Discrepant, right, from what we initially said. I had initially labeled it as a nefertic syndrome. I don't know that that holds necessarily anymore. And as I mentioned before, maybe the serum albamin being low is not from the loss of renal albammen, especially since the fractionated urine albammen was quite low. And so that was maybe a little bit of

a red herring. But this now frame shifts me a little bit into thinking more about our nefritic patterns of Injury instead of the nefertic syndrome. of what kind of um immune complex mediated diseases um or compliment mediated diseases uh might be at play. Um did you want me to get into the >> that would be great >> antipla tour? So the the what we know at least for the membranous pattern of injury what we're hear what we're seeing with me is that the injury to the ptoytes is due to um buildup of immune complexes right

beneath the ptoytes. So They've crossed beyond the basement membrane and lodged themselves right under the pto site and causing them damage and aacement. And what we've realized is that one of um the primary uh memory nephropathy is is that PLA2R is this um surface membrane protein on the ptoy that somehow and we don't know why changes confirmation and becomes antigenic. So then you have auto antibodies and anti-PLA2R to a surface protein on a pto site that is being Created and lodging itself uh right beneath the pto site and causing nefertic syndrome. So that's kind of

has helped us in the last 10 years understand a little bit more about the pathophysiology of of membranes. And so now we have an actual biioarker where we can test uh the blood for levels of antipla2. And if that is elevated in the setting of clinical nefertic syndrome, we kind of know uh with even without a biopsy that that's probably what we Classify as primary membranous neuropathy. Yeah. So, I think that I would love a urine sediment maybe exam. I don't know if you're going to give that to me before a a biopsy, but um

this is seeming more infectious and and and autoimmune uh in nature. >> Great. So, that's that's all she wrote actually. >> Oh, interesting. >> I'm sure somebody did spin the urine, but it's um this is all we have for right now. >> Okay. Well, I mean with that with someone I mean I would talk with our rheatology colleagues and see a little bit more about in a gentleman in his 50s who is uh perhaps presenting denovo. It's it would certainly be an atypical presentation of lupus nephritis um in someone who's having multiorgan injury And cerositis

and um um paricarditis all the classic things that you would think about with systemic lupus um with the low compliments. I think that that would probably be the leading kind of on the differential is lupus nefritis and then if you're going into what type of um classes it would probably be like a class three maybe a class 4 lupus nitritis picture on the biopsy um as kind of a thing to wait put my hat on or hang my hat on for at this Point. >> Great. >> It's probably not lupus nephritis, right? Oh, okay. Okay.

else was wrong when he said it's never lupus. >> I know. I know. It's always there. >> And it was class three, class 4. >> Okay. >> Can you tell us a little bit about what that means? What is class three, class 4? >> Well, um so there are six classes of lupus nephritis. Uh and they're all based on um morphology that you see on the pathology. Um and they vary uh to more severity as you get higher in the classes. So class six is kind of endstage kidney disease. all you really see is sclerosis

and scar tissue that's there versus class one where um when you look at the kidney there's no actual infiltration of inflammatory cells there But you'll see on EM that there's some accumulation perhaps of um of immune complexes that are only available and they're not really attracting inflammatory infiltrate. Uh class three and four are what we call historically our proliferative lum um lupus nephritis where proliferative means there's too many cells in the kidney that we wouldn't normally see there. And so it's oftentimes um you actually see white blood cells in The kidney tissue which typify itis

right nefritis of lupus. And so what we're having there is deposition of a bunch of full house immune complexes. Do you guys know what full house I always say full house but any poker players that know what full house means right it's it's three of a kind and a pair and so what you see uh our pathologists are usually staining to figure out which immune complexes are there and so on stain they'll see both IG A and M so Three of a kind staining positive and then C3 and C1Q the two complements staining positive so

you have three of a kind in a pair together all staining positive for and that's very specific towards um lupus which is this kind of autoimmune condition where you're spitting out and producing kind of polyclonal all different types of imunogloabbulins and they're all depositing and then recruiting a bunch of white blood cells into the kidney. And then class five is uh more where uh you're just getting the uh immune complexes going beyond the basement membrane in the sub epithelial space and behaving kind of exactly like membranous nephropathy but just due to so not staining for

PLA2R but um a full house kind of immune complexes that are then sitting beneath the ptocytes and and giving us a syndrome. Super interesting and I guess that explains the polyclonal gmopathy that he had on some of the Studies as well. Um yeah any questions or comments from the audience about can keep going but >> for that discussion um see >> yeah exactly I think that that is like in retrospect things that probably threw me off right when in our in our clinic uh where we see a lot of lupus nefritis. Um it's it is

uh typically a younger um female who's presenting not necessarily first with nefritis or kidney specific Symptoms but more hair loss and and rashes and cutaneous manifestations and then on a broad workup is is there. So um we do see obviously men with um lupus uh systemic lupus eriththematitosis with complicated by nefritis um and in that atypical pattern they may present a little bit later in in time and so it's rarer and it's not part of my kind of illness script for lupus nephritis but and maybe it should be but we do see it uh sometimes

and this would kind of fit In with that. >> Fantastic. Any other reflections on this winding journey that we took together? >> I think it's just it's hard obviously the um you can tell that something was wrong with the picture of the urupcr and the UACR. Um and you know I wouldn't you know I kind of led to the diagnostic of like let's talk about nefertic syndrome and that obviously anchored me towards more ptoite uh specific kind of problems but in this case what it ended up being Was more of a nefridic picture and so

reflecting back on the validity and if we're kind of stayed on our oh the UPCR is greater than 3.5 on one singular kind of test that can automatically put us down a pathway that then influences like later on and trying to regroup. So often times we do see or we do ask that we repeat the urine kind of the spot urine over time as things can kind of vary and influence um that exact value. And I Think um maybe I should have I knew that like the the low serum albamin in in combination with the

higher UPCR kind of also anchored me into going more for a nefertic picture than nephritis. So based on all the info that we have at the end, we think probably didn't have nefertic syndrome per se. >> No. No. And class three and four would uh be more in line with a nefritic picture and then class five would be in line with a nefertic picture. >> Great. Thank you. >> So now I'm going to invite to the podium um our postcase discussant um Dr. John Klein who's um an internal medicine resident here. he'll tell us a

little bit more about proteinuria. >> Hello. Is this working? Okay. So, I was a I was a member of the care team for this patient and I think it all threw us for quite a loop as you might imagine. It was a pretty complicated patient. So, I thought it'd be most helpful to kind Of talk about our approach to proteinura and the sort of diagnostic journey we went on. Um, beginning with the most relevant feature of this case, proturium. So, just starting with normal physiology. So normal urine excretion is generally less than 150 milligrams of

total protein and then specifically less than about 30 of albumin per day and then again a lot of what we talked about during the case of Dr. Carlos also is talking about what is the protein. Okay, Like what is what is the composition of urine protein? So we have albumin which generally makes up 30 to 40% although this is all kind of variable. There's TAM horsefall glyoproteins and other tubular proteins and then there's a mishmash of usually IG and light chains and other sort of miscellaneous proteins that are involved in the urine. Proteinura generally begins

can begin in the outpatient setting with things like urine dipsticks. Although these are Non-quantitative they're just screening tests for is proteinuria present or not and they should almost always be followed with quantitative measures if abnormal. Generally we start with the urine protein creatinine ratio which we call abnormal that's greater than about 150 and then as we heard a lot about elevated alabun is often the earliest marker for spec that's specific for glomemeular damage. And jumping just into urine dipsticks, you know, we Always anyways we always see like trace one plus 2 plus 3+. These are

general sort of guides for how to interpret these like um uh summary um summary figures. Um but just know that I'm distics and UAS that all of these 1 plus 2 plus 3 plus measures are can be influenced by things like contrast by alkaline urine by gross hematateria if present as well as also the concentration of the urine and the specific gravity Because we all love algorithms here you can kind of distill this into a pathway for how to kind of think about proteinuria. So you begin with concern for proteinuria. You have some sort of

positive metric either a dipstick or some other feature and then you can assess that with a quantitative assay often a UPCR or a 24-hour urine protein and often at that point the first decision is is hematia present or are there other features that are more Concerning for a nefertic syndrome and in that case that can lead us down the different routes. In the case of hematia we think about things like nefritic syndromes as Dr. Carlos mentioned lupus nefritis class 3 and class 4 often present with an afritic syndrome and then other classic things like an

IG nephropathy uh postprotocal glomearial nephritis and thing genetic conditions like Alport syndrome there are non-glomeular causes that are often uh Can be benign so things like orthostatic proteinura or more tubular damage uh like things like acute interstitial nefritis going down the nefertic route we can think of both primary causes of nefertic syndrome like uh minimal change disease or FSGS as well as secondary causes like lupus nephritis specifically class 5 in this case or things like diabetic nephropathy or amaloid and then going into like what's the actual uh ideology the pathogenesis um There's this diagram that

I found quite helpful from Ambos actually on the top you can see that the way that the glomeilus usually works it has ptoicytes which we heard a lot about um and also has endothelium and glomeular basement membranes um can you actually see oh yeah Perfect. So in nefertic syndrome the primary defining feature is ptoicy damage right. So ptoicytes here are damaged by some sort of process which leads to leakage of proteins from the Endovvascular luminal space into the interstissium [snorts] um causing the protein loss. And then in contrast nefritic syndrome often has uh immune complex

deposition and inflammation that destroys both ptocytes. It damages pocytes as well as a bl basement membrane leading to extravisation of red blood cells. What's also important to remember is that nefritic syndrome and nefertic syndrome can exist on kind of a spectrum. Whereas in the nefertic Syndrome you have often uh heavy proteinuria, you have hypo albinmia and you have hyper lipidmia. And then on the other extreme for nefritic syndrome you hematia and oftentimes you find hypertension. These things can also coexist. We went over this. The three primary criteria for u nefronic syndrome again are an elevated

uh urine protein hypoalenemium peripheral edema which uh we'll talk about more but they al may Also have elevated cholesterol increasing clot risks uh increasing infection risk and then uh hyponetriia as well. Um and if you recall for our patient we had a lot of discussion about the urine protein create urine protein creatinine ratio the albammen and his exam was notable for diffuse anosarka. [snorts] All of these things are consistent with nefraic syndrome, but it's also important to remember that these assays Are at single points in time. And that's important in cases where um patients aren't

fitting our diagnostic schema that we repeat these assays over time and we see how urine like these um characteristic diagnostics change. Jumping into what causes nefronic syndrome, they often arise from pathology within the glomemeilus itself from the proximal tubules or from overflow pertinent area either from the overp production of proteins um that Overwhelm tubular reabsorption capacity in the cases of things like multiple myyoma or an um they can be both transient and benign. often they can result very transiently from extreme physical stress or they can be or uh very benign presentations for things like orthostatic

proteinurium. They're also can be quite pathologic uh and these can be broken up to primary and secondary causes. Um in terms of primary causes we have minimal change disease uh FSGS we have membranous neuropathy memoriferative glomephritis and then quite rare aminoacttoid glomeritis. And then in terms of secondary causes of nefertic syndrome, we have systemic diseases like diabetic neuropathy, amaloidosis and lupus nephritis specifically class 5 as well as infections um specific drugs and toxins and then malignancies uh like solid Tumors and hodkins lymphas can all present like this. In terms of the diagnostic workup, we'll hit

the highlights here. Um generally in cases of proteinuria um you'll want to start again of course with your analysis a UPCR a UACR and a UPEP all of which is trying to get out what is the protein that is present in the urine that we're losing. Okay. Uh it can also be quite helpful for our renal colleagues to spin urine and to look for dysmorphic RBCs And RBC's casts which can help kind of point to the specific nature of the of the renal injury. From a serum perspective, looking at things like albamin, creatinine, SPEP, serum

free light chains, as well as a variety of infectious and autoimmune studies is also um part of a standard workup. And then really just considering whether or not membranous nephropathies on the differential and sending that anti PLA to our antibbody. And then from an Imaging perspective, um renal ultrasound can sometimes be helpful, but really the gold standard is a is a kidney biopsy to help define the mechanism of the renal injury. And then in terms of treatments uh we didn't have enough time to go very deep into them but for primary nefotic syndromes often we

think about things like immune suppression involving steroids cycloposphomide MMF calcurine inhibitors inhibitors and oftentimes we try and do aggressive hypertension Control and ras blockade treatment for secondary causes often involve treating the underlying cause. In the case of diabetic neuropathy you treat the diabetes in the case of amaloid you try and treat the underlying plasm cell disrasia. In the case of SLE, you often start if it's a very severe acute player with pulsetostereroids and transition into maintenance steroids. And then you can think about steroids varian therapies like hydroxyclorin calcurine Inhibitors and more recently um specific directed

amunotherapies like bellumab which is an antibbath um antibbath antibbody which is a self-service protein on B cells antibbody producing B cells and then although I think the data is a little bit mixed you can also consider dietary sodium and protein restriction for symptomatic relief from the edema. Thank you. So, in our last few minutes, we'll summarize the case and then um if Anybody has any other questions or reflections, happy to take those. Um I'd like to just also give a hand to our discussant, Dr. Carlos. That was that was fantastic. Um thank you again. So

this patient um like uh John had said was started on a steroid burst and taper cycloposomide and bimumad and his cytoenias um improved as did his doublestranded DNA. Um but he continued to have proteinura and was started on the uralupus protocol Uh with hydroxychloricquin with improvement. So he is overall doing well. Thank you so much to our wonderful chiefs who helped to prepare these slides. And thank you so much for for being here. Questions, comments, happy to pass the mic around. I can I can try to Sure. And I can repeat it for the people

online too. Yeah, go ahead. >> I heard this is for Dr. Co. Thank you so much for your discussion. I really love hearing about the protein discrepancies nephropathy. I've heard that just the serum marker of PLA R2 alone can um avoid >> specific enough remember is that true or >> the question was whether um the anti-PLA2 receptor antibodies specific enough to obviate biopsy >> uh hello can you hear me? Yeah. um they've done the studies where they've Seen the how many uh biopsies that in a patient with nefertic syndrome and a detectable anti-PA2R uh tighter

in their blood um how frequently it ended up being PLA2R positive memory and it was over 90%. So at this point it's pretty uh consistent with um you like you can go ahead and proceed with treatment which is largely steroid based because the pre-est probability of it being the biopsy showing memorathy with a with all those clinical features is pretty high At this point. That's good. >> Great. Thanks for the question. >> Well we can we'll wrap up now. Happy to take other questions at the front and and thanks again to our discussions. >> Thank

you. Appreciate it.