CME-MOC

Time Stamps

  • 03:19 Evaluating Proteinuria 
  • 09:37 Questions to narrow ddx of nephrotic syndrome
  • 22:31 Who to biopsy 
  • 31:47 Edema Management 
  • 37:16 Thrombosis Risk

Amboss Article on Nephrotic Syndrome

Show Notes

Pearl 1: Don’t be fooled by the UA!

  • Review of urine dipstick vs. UA
    • Urine dipstick: done at bedside, not looked at under microscope but rough sense of protein, blood, pH, spec grav, LE/nitrites, ketones, glucose, bili
    • UA: done in lab, microscopic exam of WBCs, RBCs, casts, crystals
  • Don’t brush off +1 protein or “few” RBCs
    • Despite some evidence for the contrary, anecdotally, nephrologists and primary care physicians alike have been fooled by the dipstick before. For example, low levels of proteinuria on the dipstick turning out to be nephrotic range proteinuria.
    • Think of the protein on the dipstick as a screening test that requires further quantification
  • Don’t ignore the specific gravity
  • Follow-up with a UPCR (urine protein to creatinine ratio)

Pearl 2: Key questions to ask a patient with new nephrotic syndrome

Pearl 3: What a generalist needs to know about a kidney biopsy

Pearl 4: Practical management of the edematous state

Pearl 5: Anticoagulation in nephrotic syndrome

  • Highest risk of thrombosis with membranous nephropathy
  • Risk of clot is inversely related to level of albumin
    • per KDIGO, albumin <2.5 should warrant consideration of anticoagulation
  • Prophylaxis or treatment generally done with warfarin or LMWH
    • DOACs have not been adequately studied in this setting
    • Of note, no RCTs have studied if patients with nephrotic syndrome benefit from anticoagulation

Transcript

Samira: The more A textbook example of that is you have a new patient with nephrotic syndrome. You do a biopsy and then you find membranous and then you have to– then you realize the patient hasn’t had a colonoscopy in 15 years, and then you made a diagnosis of colon cancer from the nephrotic syndrome.

M: Thank you to Dr. Samira Farouk who dropped that little nephro nugget. Dr. Farouk is a transplant nephrologist at Mt. Sinai, co-founder of NephSim and co-host of Freely Filtered podcast. 

S: Yeah that story really gets at those detective diagnostic strings! Nephrotic syndrome can really make you feel like the Sherlock Holmes of medicine. 

M: And with that welcome to Core IM 5 pearls podcast, this is Dr. Marty Fried, a primary care physician at  THE Ohio State Wexner Medical Center and Dr. Shreya Trivedi, an internist at BID.  Today we are covering nephrotic syndrome. 

S: And we are joined today by Dr. Clem Lee, med-peds superstar at Penn who has helped us tremendously on this episode and several others.  Thank you and welcome Clem! 

C: Excited to be here — and to finally get this going after MONTHS of working on this episode

S:  Also to make this episode possible, Core IM has been doing a lot of work behind the scenes with Amboss, which is also a medical education platform for all levels 

M: If you’re looking for something more comprehensive than our 5 pearls, we will link the AMBOSS article about nephrotic syndrome in our show notes

S: Yeah, I also just wanna give a shout out to their evidence-based On-Call Survival Guide and acute management checklists– its pretty neat. And they have a free trial on amboss.com if you wanna lurk around and see if its right for you!

M: Let’s get started on the questions we’ll be covering today.  Test yourself by pausing after each of the 5 questions.  

S: Remember, the more you test yourself the deeper your learning gains. 

  1. Urinalysis 101
    • What are the important features to not ignore on the urinalysis, especially when evaluating proteinuria?
  2. Nephrotic-range history-taking 
    • Once nephrotic-range proteinuria is identified, what questions can help narrow the differential diagnosis?
  3. Kidney biopsy
    • Which patients with nephrotic-range proteinuria should we biopsy, and how can we optimize patient safety prior to kidney biopsy? 
  4. Management of the edematous state
    • How can we manage edema in patients with nephrotic syndrome? 
  5. Nephrotic Syndrome and risk of thrombosis
    • Which patients with nephrotic syndrome are at increased risk of thrombosis, and what should we do about it? 

Pearl 1: Urinalysis 101

S: Alright Clem let’s start with a case

C: Sure – so your primary care patient is a 50 year-old woman with diabetes presenting for a hospital discharge follow-up visit for recent pyelo with a “dirty UA”. She’s doing clinically better and today before being roomed a urine dip is repeated in the office which  shows ongoing 1+ protein. What should we do with this information?

M: So the first thing I might do is throw a little shade on the reliability of that point-of-care urine dipstick. There’s just something about that little receipt that I just don’t trust… 

S: Not so fast there Marty… there is actually some interesting data out there to suggest that the automated dipstick tests are fairly accurate. One study found a nice correlation btw more protein on the dipstick and the likelihood of having a protein-creatinine ratio of 1g or more! 

C: But while there’s a pretty good correlation, the test probably isn’t good enough to ignore low levels of protein on the UA.  I’ve heard nephrologists say that even they can get fooled by the UA.

Samira: I think one nice way to think about the urinalysis protein, which is reported as usually a +1, +2, or +3, is more of a screen rather than a quantitative test. I’ve definitely seen cases where a +1 proteinuria turns out to be nephrotic-range proteinuria. I think when the urinalysis is negative for protein I feel pretty confident in the performance of that test. But I think anything more than that, anything that’s in the positive range to me warrants a little bit more investigation in quantification.

S: Ugh I can’t speak to the number of times I’ve brushed off a +1 or +2 proteinuria in an otherwise bland urine and chalked it up dehydration or transient proteinuria. OK so if we should be thinking about protein on UA as more of a screening test, then whats the next step to quantify that protein more? 

M: Turns out its the spot urine protein-to-creatine ratio – sometimes shortened to the UPCR 

C: Yes, upcur.  So sometimes you’ll hear nephrologists talk about the urine albumin ratio. The important thing to consider for this is that the albumin ratio is going to miss urine light chains in the setting of myeloma kidney, so some folks prefer the upcurr for that reason… 

Matt: If we could have a reflexive test to hit every time you have a trace or any one plus two plus three plus proteinuria on a dipstick, you automatically get that ratio because then the ratio is very important to quantify that. 

M:  That’s  Dr. Matt Sparks, the APD for Duke Nephrology.  He is also on Freely Filtered podcast and is the co-creator the famous Neph Madness competition.  

S: Ok maybe one day Dr. Sparks’ dream of a protein-creatinine ratio reflex test will exist but for now so how do we optimize that urine protein creatinine ratio collection? 

C: Tell your patients to get it collected in the morning. This is a throwback to our albuminuria episode since there can be transient orthostatic proteinuria that’s lessened when the patient’s been lying down all night. And when you do get the results back, pro tip: take a peek at the specific gravity.

Matt: I can mention one interesting tidbit. So I usually, uh, look at the specific gravity and sort of, uh, eh, you know, what is the use of that?

M: Oh man, so happy to hear that I am not the only one who thinks that… go ahead Dr. Sparks

Matt: However, I was confronted with a nice board question a few days ago, where I had a patient that it had lupus, everything looked fairly stable on the individual, except for the amount of protein in the urine increased from a very low amount, like a hundred milligrams per day, to about 300 milligrams per day.

And one of the parts of the question that you would might have skipped over is that the specific gravity was completely different in the second specimen compared to the first one. And that urine was very dilute. And so the answer was to do a 24 hour urine in that specimen because you might’ve had a falsely low value and the person might actually have even more proteinuria in that case. 

S: Now thats a tricky Q! So sounds like concentrated urine may falsely elevate proteinuria, and dilute urine is going to falsely decrease proteinuria. 

M: Great.  So when we are interpreting the UPCR,  what numbers get the nephrologists really jazzed up about possibly finding someone with nephrotic syndrome? 

C: So 3 to 3.5 g/day is the magic number here to define nephrotic-range proteinuria. Not to be confused with nephrotic SYNDROME, which is nephrotic-range proteinuria but with also low albumin (< 3.0) and peripheral edema.  Sometimes this is associated with hyperlipidemia and thromboses, but not always. 

M: Alright, so that’s it for Pearl 1 about urinalysis basics.  Think of any proteinuria on a UA as a screening test that should make us consider further quantification with a urine protein-to-creatinine ratio.  And don’t overlook the specific gravity either as that might give you an even stronger indication for quantification, for example if you are seeing increasing protein on the UA despite a low specific gravity which mean dilute sample. Once you hit 3 – 3.5 g/day of protein your patient is now in the nephrotic range and the next line of questioning and evaluation is geared toward evaluating for nephrotic syndrome, which Clem beautifully summarized is nephrotic range proteinuria with low albumin and edema. 

Pearl 2: Nephrotic-Range history taking

S: So back to our patient, now that we know we aren’t just going to disregard her UA thinking its transient or oh she was in the hospital, we can either repeat the UA or get the urine-protein-to-creatinine ratio

C: We end up sending the UPCR and her ratio ends up being 4.5 grams protein per day… ooof. During her last visit with you the routine BMP and annual urine albumin-to-creatine ratio for diabetes had been completely normal.

M: Dun dunn dunnnnnn.  Shrey – how much you want to bet this lady is going to have nephrotic syndrome?  

S: [nervous laugh] I think there’s a quite strong chance on this episode Marty.  But before we can call it nephrotic syndrome, we gotta assess for low albumin and edema too. And most importantly putting our thinking caps on

Samira: Usually for our initial workup, what we’re really thinking about is does this presentation really fit more in the bucket of nephrotic syndrome or is it more indifferent syndrome type picture? There’s a lot of overlap between the two, but we can really identify patients that have a pure nephrotic syndrome by looking at the urinalysis appear nephrotic syndrome should not really have hematuria, We shouldn’t see pyuria or the presence of white blood cells in the urine. It’s really just overwhelming proteinuria.

M: Just to amplify what Dr. Farouk is saying – in this podcast our laser focus is nephrotic syndrome.

C: Yea ! We’re not talking about anything with dysmorphic RBCs or casts… or even worse… crescents! 

Samira: So if we are thinking about pure nephrotic syndrome. You want to think about primary membranous nephropathy, I’m thinking about FSGS or minimal change.

S: I really appreciate having 3 this on the differential to focus on – i feel like everytime im sitting in a presentation on nephrotic syndrome its just a bunch of rapid fire slides of each type of nephrotic syndrome and nothing sticks. But it’s relieving to hearing that i can start with these 3 potential buckets: minimal change, FSGS and membranous.

C: The alphabet soup of nephrotic syndrome is pretty intimidating, but Dr. Farouk had a bit of practical advice. 

Samira: So for all these cases ultimately will come down to the kidney biopsy findings to help us with what is the pathologic pattern.  And then we have to try to understand whether or not this is a primary or secondary process and that assessment, in my opinion, really comes from that history, getting that history and trying to distinguish whether or not these glomerular diseases that are causing nephrotic syndrome are primary or secondary is where the medical team can really play an integral role, because this has important implications for treatment for patients that have primary glomerular disease. We’re looking at high dose immune suppressive therapy, whereas in a patient with secondary glomerular disease, the treatment like anything else in medicine would be treatment of the underlying condition.

M: So the reality is that most of these patients are probably getting a biopsy, and what Dr. Farouk is saying here is that often the way you diagnose primary glomerular disease is if they don’t have a secondary cause – which is established with a good history and workup. 

S: Lets make it more practical — maybe itll be easier for it to stick for ppl like me– and lets think through when we are going down to the ED to admit a patient or in clinic, for each of these, what should we be asking and assessing for , especially if we are trying to get at an underlying secondary process causing all that protein to leak into the urine?  

M: How about we start with minimal change disease.  I typically think about it as a pediatric issue… so how do we think about it in adults?

Samira: Typically the one that has the classic full-blown dramatic nephrotic syndrome presentation within a few days, or even a few weeks, that would be minimal change disease. So commonly patients may come in a few days ago, they were feeling okay, and now they’ve come in with anasarca nephrotic range, proteinuria. So when we see minimal change disease, particularly in an adult, we’re thinking about secondary causes while a primary is possible, it’s probably a little bit less likely and so important. Secondary causes of minimal change disease include hematologic malignancies. We should also be thinking about drug induced, minimal change disease, a commonly used medication are nonsteroidals. And so though we classically learn in medical school that this is associated with acute interstitial nephritis, this is often accompanied by nephrotic syndrome.

C: Ok big takeaways for minimal change – remember this is mostly a pediatric disease, but in adults ask your patients if they have been loading up on NSAIDs or if they weight loss, fevers, sweats that may point to a malignancy, classically Hodgkin lymphoma.  But keep in mind if you don’t find anything you’ve actually found the most common cause, which is idiopathic. 

M: So lets move on to FSGS – or focal segmental glomerulosclerosis.  A pathophys pearl here is that minimal change and FSGS are similar pathologically – they are both podocytopathies for you future nephrologos out there – and the two can almost be thought of as occurring on a spectrum. Just tuck that away for a little snack for later.  

Samira: FSGS can sometimes be the hardest one to differentiate between primary and secondary, even for pathologists, because many of the features are overlapping. And the other complicating factor is that many other causes of kidney injury, including other glomerular diseases can end in FSGS type picture because end stage kidney disease, essentially our sclerosis glomeruli, which is what we see in different stages of FSGS.

M: And because we can’t just rely on the biopsy, this is where history is going to help us here. 

Samira: And so it’s really important in those patients to kind of have a better understanding of the time course, the full history. Um, and common secondary etiologies of FSGS are diabetes, hypertension, obesity.

M: Another secondary etiology I remember as a terrified new attending was a patient with congenital solitary kidney who developed nephrotic syndrome, and the renal attending used the term adaptive FSGS – a term I had never  heard before – referring to hyperfiltration-related injury leading to FSGS.

Samira: We know that patients that have needed a nephrectomies in the past often develop focal segmental glomerulosclerosis in the other kidney due to what we call hyperfiltration injury. So the idea is that you take out the one kidney, but then the other one is kind of dealing with an increased filtration load. And so I think that a similar theory is thought to be playing a role in obesity and that you kind of in general have this hyperfiltration because of increased body mass and size. And this leads to a large glomerulus or glomerulomegaly.

S: I am continuously amazed at the impact of obesity on the body, even on the glomeruli! But what other systematic things lead to FSGS?

C: So so many. Remember that FSGS is a pathologic diagnosis, a common end point to many many disease processes. Heads up, Dr. Farouk is about to drop A LOT  of knowledge. So try to catch as much as you can, it’s always fine to go back and look it up again. 

Samira: Some of the more common ones are HIV, which you’ve mentioned parvovirus though. Many other viruses have been implicated even if only in case reports, for example, CMV and more recently COVID-19 has been associated with secondary FSGS. There are many common commonly administered drugs like this bisphosphonates that can cause a very dramatic collapsing FSGS … heroin use, interferon use can also lead to a glomerular injury and an FSGS type thing. 

Matt: I think the other thing with FSGS that’s very interesting is the familial or inherited FSGS’s, which are very rare, by getting a family history and seeing that you have a pretty high prevalence of kidney disease in a family 

C: Ok so takeaway for FSGS is to look for the 1. metabolic syndrome – (obesity, Diabetes, Hypertension) – 2. scary viruses like HIV and SARS-CoV-2, 3. a family history of FSGS or patients with solitary kidney and, lastly, looking for certain drugs like bisphosphonates and heroin. 

S: Ok Let’s finish up the “big three” with membranous.  Unlike the other nephrotic syndromes, membranous has a nice antibody test to keep in your back pocket to distinguish primary vs. secondary.

Samira: Phospholipase A2R receptor that’s present in the podocyte. So patients that have antibodies against that are going to be directly attacking the podocyte and causing injury. A positive titer of that antibody, which is an antigen in the podocyte would be strongly indicative of primary membranous nephropathy.

S: I honestly didn’t know how strongly the data is for a positive antibody titer phospholipase A2R and its link to primary membranous nephropathy & nice get clear answers but if phospholipase A2R antibody is negative and what are we assessing for secondary disease process can cause membranous nephropathy?

Samira: Screening for, for cancers that would be age appropriate. So for example, colon cancer screening, breast cancer screening, lung cancer screening in an active smoker. Um, hepatitis B is classically associated with membranous nephropathy. Common infection that’s associated with nephrotic syndrome is syphilis can cause a secondary membranous nephropathy. 

Matt: And if you did all of that you would have a massively nice letter for your fellowship from nephrologists. That would be an amazing workup right there. 

M: Boom – you heard it first, listen to the podcast, drop an amazing workup for a patient with nephrotic syndrome and get a letter of recommendation from your local nephrology team.  Feel free to cite Dr. Matt Sparks in his Core IM debut when you tell all your friends. 

S: Well, mayyyybe don’t cite Dr. Sparks there, but listening to Dr. Farouk’s membranous workup is a thing of beauty.  Especially because you wouldn’t want to start a treatment on someone and find out later there was another treatable process that could have led to podocyte repair and and resolution of nephrotic syndrome. So to recap for membranous, we are likely sending off a anti-PLA2R antibody – the new kid on the membranous block – as well as checking for age-appropriate cancer screening, and a few STIs including HBV and syphilis.  Oh one thing that wasn’t mentioned- lupus.  

M: Can’t forget lupus. 

S: Really can’t go wrong with tagging lupus on to the end of any sort of differential diagnosis.  

M: Ok and besides minimal change, FSGS, and membranous, we shouldn’t forget three other really important causes of nephrotic syndrome.  First is amyloidosis.

C: Next is preeclampsia… which I specifically went into med peds to NOT think about.

S: And then, last but not least, the MOST COMMON cause of nephrotic range proteinuria… diabetes! 

M: Pretty amazing it took us this long to mention… 

C: Ok, let’s summarize this beast of a section. 

M: (exhale deeply) ok, I got this…. Ok I don’t know if I got this

S: No worries Marty, I got you. So practically speaking for minimal change disease we should ask B – symptoms and about over the counter meds use with NSAIDS, for FSGS, we will also look over their med list but for bisphosphonates, ask about substance use history and family history of renal problems, think about metabolic syndrome is playing a factor, pretty much everyone is getting a COVID brain message so I’m not worried about that but ill add in HIV screening, if they have 1 kidney or are obese, think about that hyperfiltration-related injury for FSGS and lastly to put membranous higher or lower on the ddx, ill get the anti-phospholipase 2AR receptor, think about hepatitis B and syphilis and ask about age appropriate cancer screening. 

Pearl 3: Kidney Biopsy

S: Ok – Clem, let’s keep our case going.  

C: Our patient denies any family history of kidney disease. She denies illicit drug use and is not on any medication other than metformin. She is sexually monogamous with her wife. She just got her screening colonoscopy, which was normal. We end up referring her for a kidney biopsy.

M: Listening to Dr. Farouk in the last pearl… am I the only one channeling Oprah here… ya know, like “You get a biopsy!  You get a biopsy!  EVERYBODY GETS A BIOPSY!!!!”

S:  Someones going to make a meme out of that!

M: No doubt.  I definitely have had an amazing old school nephrologist tell us that he was taught only to biopsy to confirm the diagnosis you suspect and not to go fishing…. Which is definitely different than what we’re learning from Dr. Farouk and Sparks here and I just think it’s interesting to see how far we’ve come.  But anyway, Clem talk to me about what the guidelines say about biopsying specifically for proteinuria. 

C: Yeah so a few indications mentioned by NKF would be proteinuria > 1g/d on multiple visits over time and > 3 g/d even once.  And the caveat here is this is in patients without diabetes.

S: Ok, but what about half of my prior patient panel if your patient has diabetes and some proteinuria? 

Samira: Classically we say that diabetic retinopathy should precede diabetic nephropathy and so if you have a patient without retinopathy, maybe think about another cause of glomerular injury.

C:  Despite that classic teaching, Dr. Farouk did point out that in real life, a significant proportion of patients, up to 30% in some case series, can actually have nephropathy before retinopathy, so don’t live and die by these rules.

Matt:  There’s definitely situations in clinic where you’ll follow some individual that has diabetes and they’ve had it for a while. But they don’t have retinopathy. They don’t have peripheral neuropathy, but they have like eight grams of proteinuria. And I want to know if there’s anything else that’s happening with this patient that I could potentially help preserve kidney function. And so even though the biopsy might end up showing diabetes and diabetic nephropathy, it puts me a lot better ease to say, all right, you don’t have X, Y or Z glomerular disorder. You do have diabetic nephropathy, but occasionally you’ll find something that just, you never would have even imagined.

S: Ok so it sounds like 8g/d of proteinuria is TOO much for “classic diabetic nephropathy” but 1g/d of proteinuria is NOT enough…. So when exactly does diabetic proteinuria cross into that “too much gotta biopsy” realm? 

Samira: I think overall diabetic kidney disease is grossly under biopsied. So I think we just don’t really know what we’re dealing with, especially when it comes to earlier disease. Um, with respect to when is the proteinuria too much? I think like anything else in medicine is kind of the change.

Matt: So it’s that Delta change that’s very important. Uh, so someone having a 300 milligrams per deciliter of a protein and all of a sudden has two grams, can be a significant finding, whereas another individual that’s had six grams for years might not be, uh, at, um, you know, as big of a deal. So you have to sort of look at each patient separately and, and so the, the number, uh, might be, uh, you know, arbitrary 

M: You get a biopsy and you get a biopsy and everryyyboddyyy gets a biopsy! 

S: Oh my gosh Marty.  But takeaway is that diabetic nephropathy usually progresses gradually over a – some say at least over 5 years or so – vs. some of these other primary or secondary causes of nephrotic syndrome will be a bigger delta jump over time in the proteinuria — but there isn’t a magic delta number to guide us.  

C: So that about wraps up patients with diabetes. Another important group to biopsy are those folks with minimal change disease who don’t get better with steroids.  And this a throwback to how Marty mentioned earlier that minimal change and FSGS are related – you may think you’re dealing with one of them but you’re actually dealing with the other…

Samira: There is a discussion that there’s maybe a spectrum that goes from minimal change up to FSGS and that even though your biopsy specimen looks like minimal change, that you maybe just missed one of those sclerotic lesions. Because for the diagnosis of FSGS, you really just need one sclerotic lesion in one glomerulus to make that diagnosis. So there may be a significant contribution of sampling bias. So if we have a minimal change disease patient that we expect to improve and they don’t, the threshold will be pretty low to consider a second biopsy to confirm the diagnosis.

M: Clem – you’re not leaving this podcast until we freakin’ biopsy your kidneys 😜 (C: Marty… what are you doing with that 18-g needle…)

S: Hey now hey now, there will be no RP bleeds on my watch.  But all this biopsy talk brings up the elephant in the room – how safe are kidney biopsies? 

Samira: In general, I would say that kidney biopsy is a safe procedure… The complications that we’re worried about are risks of bleeding…. So, what are the complication rates? What I tell my patients is that the rate of a bleed is probably less than 1/100 to 1/1000. And the rate of a bleed that requires a procedure is even lower than that. And the rate of a bleed that’s going to lose that kidney is minuscule. 

S: You know I gotta be honest, it was a little surprising for me to  hear nephrologist put kidney biopsies as being so safe because I think we have all been scarred by an M&M conference of a biopsy that led to a retroperitoneal bleed or some other complication 

C: True but if you think about it, it’s not unreasonable for there to be a little bit of bleeding if we are piercing the actual kidney with a needle. Most of the bleeding that occurs after is fortunately self-limited, and significant bleeding requiring intervention is rare, less than 1%. 

S: So I guess the next question is how to maximize safety of the biopsy.  

Samira: One is to control the blood pressure. So we would avoid doing a kidney biopsy and someone that is hypertensive; that would increase their risk of bleeding.

M: And Dr. Sparks ran through a pre-biopsy checklist that he thinks about early on in hospitalization for patients he believes will need the 18-gauge of truth. 

Matt: What’s their INR, what’s their platelets, uh, what anticoagulation are they currently on and what do we need to stop in order to prepare them for that? Can they lie flat? Because if they’re way volume overloaded, we need to start working on getting that under control with diuretics.

M: And sometimes we also need to do pre-biopsy dialysis if someone BUN is through the roof.

Samira: If you have a patient with acute kidney injury that’s azotemic their platelets may actually be dysfunctional. So for example, if my patient’s BUN is over 80 or 100, then maybe I require 2 dialysis treatments before I feel comfortable, but we know that BUN is not, you know, 100% marker of azotemia, it’s just, you know, something that we use. And so it doesn’t mean that if my BUN is less than that that I don’t have dysfunctional platelets.

S: Noted – I will peek at BUN, usually a neglected lab or as Uncle Bob would call an unremarkable lab. Either way, if we are seriously considering a biopsy, we should probably have a nephrologist on board already, especially for risk/benefit conversation with the patient and to help us think through peri-biopsy safety considerations.

M: Hah – I am more than happy to let them have that.  Alright Clem, bring this pearl home with a summary. 

C: The indications for a kidney biopsy in patients without diabetes include proteinuria of 1g/day over multiple visits or 3g /day even just once. In patients WITH diabetes, you are really looking at the change in protein over time and correlation with other microvascular complications. The rates of bleeding after biopsy are around 1%, and we can optimize patient outcomes by controlling blood pressure around the time of biopsy, consider pre-biopsy dialysis for significant azotemia and hold anticoagulation whenever possible. 

Pearl 4: Management of the edematous state

S: So unfortunately while our patient was waiting for her kidney biopsy, she was just so uncomfortable from her swelling that she went to the ER and got admitted for volume overload.

M: But the problem with patients with nephrotic syndrome is that our loop diuretics often don’t work as well!

Samira: In patients with nephrotic syndrome who may have poor delivery of diuretic because of impaired kidney function or even due to low oncotic pressure, as albumin is necessary to be able to secrete the loop diuretic into the tubular lumen. We usually start with relatively high doses of loop diuretics.

C: So we need albumin to get that furosemide to the loop of henle to do its magic but with the low albumin in nephrotic syndrome, that same dose of furosemide may not work as well as if they had normal albumin.

M: Ok, so why don’t we just give the old albumin-lasix chaser? I mean who isn’t guilty of having done this once in residency?  Give the patient a whiff of albumin to beef up that oncotic pressure and then chase with furosemide to catch the albumin wave straight into the loop.  

Samira: Albumin? short answer is no, there’s no data to support the use of albumin assisted diuresis. Um, there’s been a lot of talk about this on social media. Some of the most compelling tweets are those that say that if you do that all you produce is very expensive urine.

C: From my reading on the controversial literature, at best that albumin has a short-term benefit  of a few hundred cc more output but that effect is not seen long-term. So seems like albumin-lasix chasing in nephrotic syndrome isn’t worth it, especially from a cost perspective. 

S: Ah bummer I was really hoping something would help us out. Does how we dose lasix matter?

C: So even in healthy people, Lasix is not very bioavailable, so when you’re dealing with patients with nephrotic syndrome with gut edema, you’ll want to use intravenous Lasix. And since the onset of action is so quick, you can dose it up to 2 or 3 times a day. 

S: And on top of that higher frequency, we are probably also reaching for higher doses of diuretics. It makes me kind of worry about that side effect of ototoxicity that we learn about in medical school.

Matt: I have never seen it. And I think one of the things is we just don’t typically use as high of a dose as when it was seen. 

S: It is a bit of a relief to know that it’s rare and studies show it’s reversible. Though the fear is real and for this some clinicians like to reach for continuous infusion over time and so the patient with nephrotic syndrome is exposed to less high bolus doses.  

M: So that’s it for the diuretics, what about other tips for helping our patients manage their edema? 

Matt: I’m really big on daily weights, and so I want to teach them how to titrate their loop diuretics with my help. The other thing that I’ve found is very helpful is a food diary. I think what it does is it forces a person to really think about what they’re eating, because if they don’t write it down, they basically believe they did not eat it.

Samira: I think the number one concern for patients with nephrotic syndrome aside from, um, you know, medications that we may be prescribing is really kind of restriction of salt.

C: There’s a patient-friendly handout from the NKF that lists high-salt foods and what to replace them with. 

S:  There’s another infographic and website I really from AHA that we’ll link in the show notes because it goes through offenders that patients don’t usually think of like bread, especially yeast bread or cheese as adding up in that salt intake.

M: Those foods can really add up and yes diuretics help, but let’s not forget that probably the best treatment for these patients who are struggling with edema is to treat their underlying process.  

Matt: Well, one of the things you’ll see is it’s absolutely a miracle is when you have someone with like, let’s say membranous –  this is a patient that I had that was just anasarcic and just miserable. Couldn’t even move. And we tried high powered cyclophosphamide and prednisone. And I got them admitted one time they were so volume overloaded. And then we, and this is anecdotal, but we gave her rituximab.  And then it was like just the flood gates opened.  And the patient just, it was like they were walking on water. They just, absolutely. It was like, uh, they, a new person was born. So that’s why like getting the diagnosis and treating it is going to be a lot more effective than your diuretics.

M: Oh that is a fantastic story.  I think we should leave off there.  Clem, want to summarize this pearl? 

C: Basically you are treating the edema due to nephrotic syndrome similar to how you treat edema due to other diseases like congestive heart failure and cirrhosis.  Loops are going to be your friend but remember since furosemide is highly bound to albumin (>90%) you will likely need higher doses in an IV form.  Forget pre-gaming with albumin and coach patients at home on how to be successful with daily weights and low-salt diets. 

M: Clem… kinda sounds like you want a biopsy?

C: Sign me up! As the nephrologists say– FSGyes

Pearl 5: Anticoagulation in nephrotic syndrome

S: Alright guys, let’s minimally change gears to a brief bit about thrombotic complications of nephrotic syndrome.   

M: Yes, and, heads up folks we are about to get dangerously close to an “evidence-free zone” here, but thrombosis in nephrotic syndrome is definitely one area of management that we are still figuring out.  But, Clem, what do we know? 

C:  So we know that all patients with nephrotic syndrome probably have an increased risk of both arterial and venous thrombosis and that risk is almost definitely probably most likely greatest in patients with membranous nephropathy. 

S: Yeah the clot risk in patients with membranous is one of the “classic” associations that we should be aware of and for sure a classic internal medicine boards question.  

M: Ok, anything else we should know about clot risk and membranous nephropathy?

C: Yes.  The risk appears to be inversely related to level of albumin – meaning that as the serum albumin drops the clot risk increases.  

M: Alright so what are going with all this risk? 

S: The evidence is thin, but what most people agree on is that patients with idiopathic membranous nephropathy and low serum albumin – typically less than 2.5 mg/dL – should get prophylactic anticoagulation.  

C: Right but another conundrum is which prophylactic blood thinner to use.  Typically DOACs are not used in favor of warfarin or low-molecular weight heparin, but this is mostly because of the available data. So the big takeaways for thrombosis in nephrotic syndrome are (1) thrombosis is more likely in patients with membranous nephropathy and/or hypoalbumenia and (2) if we are going to prophylactically anticoagulate we can use warfarin or low-molecular weight heparin 

M: Nice!  

C/S: Bye! 

And with that’s a wrap for todays episode. If you want to learn even more about nephrotic syndrome, check out the corresponding article at Amboss, linked in our show notes. If you found this episode helpful, please share with your team and colleagues and give it a rating on Apple podcasts or whatever podcast app you use! It really does help people find us! 

If you want to add any of your own tips or share challenges, tweet us and leave a comment on our website page, on instagram or facebook page Thank you to Dr. Rahul Maheshwai  for the accompanying graphic, to Solon Kelleher for audio editing, to peer reviewers Drs. Swampnil Hiremath, Gerren Hobby, Tejas Patel. And thank you to Dr. Mary Guan and Dr. Vipin Vargese for off-air producing this episode.

As always we love hearing feedback, email us at hello@coreimpodcast.com. Opinions expressed are our own and do not represent the opinions of any affiliated institutions.

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