Precious Bodily Fluids

Norris Jackson is something of a hero around Detroit. He was the first security guard at the Detroit Symphony Orchestra and remained their security guard for 34 years until he retired in 2023.

https://www.cbsnews.com/detroit/news/beloved-detroit-symphony-orchestra-security-guard-retires-after-34-years-of-service

Retirement didn’t slow him down. His Motor City Rams just won the Player Football Association Midwest Championship against their crosstown rivals, the Detroit Ravens.

But that wasn’t the Norris Jackson I knew. I knew the patient with severe hypertension and advanced chronic kidney disease.

I met Norris in 2019 when he was admitted with a blood pressure of 204/102, a creatinine of 5 mg/dL, and a potassium of 6.2. His prior creatinine from a year earlier was 3.4 (his whole story hinges on this earlier creatinine). We diagnosed him with hypertensive emergency, with AKI as the end-organ damage. We stabilized his blood pressure, but the kidney function never improved. Using the 2009 CKD-Epi race based formula his GFR was 13 ml/min. Using the current race-free 2021 formula it was 12 ml/min.

It is always hard to start the CKD journey in Stage 5. We were going to have speed run the advanced CKD playbook. He followed up in my clinic a couple of weeks after discharge and his blood pressure was improved to the 160s systolic. We referred him to transplant and cardiology for transplant clearance.

He returned a month later and his blood pressure was in the 140s. Cardiology started their work-up by scheduling an echo and a stress test with nuclear imaging. We increased his torsemide to 100 mg daily.

By June we had his blood pressure down to 127/60 on torsemide 100, chlorthalidone 25, nifedipine 60, and hydralazine 50 bid.

His transplant quest had the usual problems of collecting reports from other hospitals systems, dealing with a positive TB skin test, and completing multiple tests and imaging requests.

We also started him on epoetin and regular iron infusions. It was a lot but Norris did it all. Then a year after I met him, COVID hit and if navigating the health system seemed difficult before hand, it became near impossible during the pandemic. There will never be a full accounting how much damage was done by interrupting and delaying the care of everyone in the medical system.

Jackson wasn’t fully listed for a kidney transplant until November of 2022.

While he was navigating the world of transplant we were simultaneously preparing him for dialysis. Every visit we did modality education and discussion. He decided on home therapy and we referred to our general surgeon, Dr Meguid, who has really taken a deep interest in PD and become a valued partner. In June of 2021, Norris received a PD catheter and he began dialysis the following September. We did the whole process as an outpatient.

So by UNOS rules, even though he wasn’t listed until 2022, his wait time was backdated to the start of dialysis, September 2021.

But something else happened in 2021. The nephrology community abandoned race in the calculation of eGFR. While this change helped Black patients going forward, it did nothing for people whose transplant evaluations had already been delayed by the old race-adjusted equation. So in January 2023, the Organ Procurement and Transplantation Network (OPTN) required transplant programs to review Black kidney transplant candidates and determine whether earlier creatinine values would have made them eligible for listing using the race-free equation.

Norris had exactly that creatinine from a year before he presented to my service. This creatinine of 3.4 gave him a GFR of 21 by the 2009 formula, but with the 2021 race-free eGFR it was 19 ml/min. Low enough for him to be eligible for transplant listing.

With the stroke of a pen, his wait time moved from late 2021 to early 2018. An additional three years. This was enough to thrust him near to the top of the list.

In September of 2024, Norris got his kidney and three days later he was home with a falling creatinine, feeling better than he had in years.

A lot of people worked hard to remove race from eGFR equations. It can feel like an abstract policy debate.

But sometimes it looks like this.

Note: This was one of my first posts on Roon.com If you are an American physician who likes to chat about medicine, you should sign up.

There are so few prospective randomized trials in hyponatremia that we cherish every one, even the quirky, underpowered ones. So let’s take our hats off and salute the Royal Thai Air Force for putting the DDAVP clamp under the RCT microscope.

Safety and efficacy of proactive versus reactive administration of desmopressin in severe symptomatic hyponatremia: a randomized controlled trial

https://www.nature.com/articles/s41598-024-57657-z

The trial is underpowered: their power calculation called for 66 patients, but they enrolled 49. Still, I love that they had the courage to test something many of us, including me, have accepted without prospective data. Given the scarcity of trials, this is very much the hyponatremia way.

The investigators randomized patients to a proactive strategy (a DDAVP clamp) versus reactive DDAVP.

And they had the courage to enroll people who were actually sick. Many hyponatremia trials enroll patients with relatively mild disease, but this cohort had an average sodium of 115 mEq/L, which is impressive. Just look at the High risk of osmotic demyelination syndrome and the Clinical presentation in this population. These are the bad actors in hyponatremia—the patients who actually need randomized trials.

The HIT trial would have benefited from enrolling a cohort like this.

The results though, were similar to the HIT. There was no difference in overcorrection, 24-hour sodium change, or length of stay. The sodium rose more in the proactive group at 48 hours, but given multiple comparisons in a small trial, that signal should be ignored.

The overcorrection rate was 16.7% in the proactive group vs 28% in the reactive group (P = 0.54).

That’s remarkably consistent with MacMillan’s Toronto data, where about 18% of all comers overcorrected. It’s also far better than the 40% overcorrection rate reported by George Et al in Western Pennsylvania.

Interestingly, Pakchotanon enrolled patients with Na <125 mEq/L, neatly splitting the difference between the <130 threshold used by MacMillan and the <120 used by George.

Honestly, I expected better sodium control than they achieved. My suspicion is that the 3% saline dosing protocol in this trial was relatively aggressive. I know I tend to be more conservative with hypertonic saline when managing severe hyponatremia.

Still, this study is welcome. It’s part of a growing trend in hyponatremia research toward prospective data rather than retrospective dogma.

And in hyponatremia, every randomized trial moves the field forward.

One of the challenges in the assessment of hyponatremia is we rarely get to assess patients fresh from the community. By the time the nephrologist is called patients have usually received a liter (or two) of 0.9% normal saline. I call these sneaky IV fluids because they often don’t even get documented. Somewhere between triage and the nephrology consult a liter of saline appears—no order, no note, just a bag that quietly happened.

So when the emergency department, or ward, gets around to collecting the urine for biochemical analysis, the urine has been contaminated. Can we trust those altered specimens? Can they reliably distinguish hypovolemic hyponatremia from SIAD?

Well Dr Chienwichai of Thailand designed a study to answer that very question and he did it prospectively with a well designed rigorous trial.

He took patients with a sodium less than 130 and eliminated anyone with fluid overload. He also eliminated people where the urine sodium cannot be trusted:

• Nobody who received fluids before he got a chance to assess urine and blood
• Nobody on diuretics
• Nobody with adrenal insufficiency
• Nobody with metabolic alkalosis or even just a serum bicarbonate over 30
• Nobody with an eGFR less than 60

And then after checking basic urine and serum biochemical profiles ran everyone through protocolized fluid resuscitation. If the serum sodium failed to rise or fell with saline, patients were categorized as SIAD.If the sodium corrected with fluids and remained corrected when fluids were stopped, they were categorized as hypovolemic hyponatremia. The protocol looked something like this:

So at the end of the protocol they had the cohort convincingly divided into SIAD or hypovolemic hyponatremia. And they had a record of:

• Their initial urine and serum biochemical profile, Time Zero
• Their urine and biochemical profile after 500 ml, Time One
• After one liter, Time Two
• After two liters, Time Three
• and after four liters, Time Four

And so now we can see if that sneaky liter of saline ruins the biochemical tests. And you know what? It actually does the opposite. It makes the difference between SIAD and hypovolemic hyponatremia more stark. Here is table two with the averages:

So it is pretty clear that the numbers don’t meaningfully change with saline infusion but what I’ve been trying to explain in my recent lectures the urine sodium isn’t the window to truth we sometimes expect it to be. This question can be seen in Figure 2:

Though the numbers don’t lose information (and actually gain separation) with fluid resuscitation, there remains tremendous overlap with the urine Na between hypovolemic hyponatremia and SIAD. This is beautifully shown with the ROC curves the authors provide:

While an AUC of 0.75 is quite a bit better than 0.61, it’s helpful, but far from diagnostic.

One of the findings of the study was that patients who ultimately are diagnosed with SIAD often had an initial positive response to saline infusions:

However, our study showed that urine osmolality also decreases in SIAD from before saline infusion to after saline infusion. We hypothesize that this may be due to the vasopressin escape mechanism, a defense response characterized by increased urine volume and decreased urine osmolality. Furthermore, concurrent hypovolemia in hospitalized patients may have contributed to the observed decrease in urine osmolality. Although a decrease in the serum sodium level after saline administration is used as supportive criteria for diagnosis of SIAD25, approximately 30% of patients with SIAD have been reported to experience an increase in serum sodium by 5 mmol/L after receiving 2 L of 0.9% saline. In our study, this was observed in 38% of patients with SIAD.

I’ve seen this many times. SIAD can give a head fake by initially responding to saline. The sodium rises, everyone relaxes, and we think we were just treating volume depletion—only for SIAD to reappear a day later. It was satisfying to see that this was a real phenomenon rather than an undocumented spook.

The last finding I want to highlight is uric acid. I’m a fan of serum uric acid, and some of my fellows have been waving the flag for fractional excretion of uric acid (FEUA). However, in the baseline labs there was no significant difference in serum uric acid between hypovolemic hyponatremia and SIAD. FEUA did show a difference, but there was still substantial overlap. You can see this in how high the 75th percentile of FEUA was in hypovolemic hyponatremia, 13.9, even though the commonly cited cutoff for SIAD is only 12%.

The take home message:

Don’t panic if the urine studies were drawn after a liter of saline. The saline doesn’t destroy the diagnostic signal. If anything, it may accentuate the physiologic differences between hypovolemia and SIAD. And most importantly: urine sodium is helpful, but it is never the whole story.

The Hyponatremia Interventional Trial (HIT) has been published in NEJM Evidence. The results were unveiled at the Late-Breaking and High-Impact Clinical Trials session at ASN Kidney Week 2024 in San Diego, and we’ve been waiting 15 months for the manuscript to drop. Last week, it finally did.

https://evidence.nejm.org/doi/full/10.1056/EVIDoa2500086

The NEJM Evidence Journal has now published three of the most important articles on hyponatremia in the last few years. First with MacMillan Et al. that showed that CPM was quite a bit rarer than previously thought. Then the NEJM Evidence struck again with Seethapathy Et al. who showed that patients with hyponatremia who corrected at the slowest rate had higher hospital mortality. And now the HIT.

The premise of the HIT was straightforward and compelling. Hyponatremia has long been associated with worse outcomes: higher mortality, more rehospitalizations, longer lengths of stay. But association is not causation. So the investigators asked:

What if we deliberately and systematically corrected hyponatremia? If we do a better job at improving hyponatremia in one arm of a randomized trial and outcomes improve in that arm, that would go a long way to prove that hyponatremia is directly responsible for those adverse outcomes?

To test this, they randomized 2,100 patients to either standard care or a strategy of multifaceted targeted correction of hyponatremia. I would describe the intervention if it was describable but what it essentially comes down to is “consult nephro and have them run the hyponatremia playbook as described in Verbalis’ 2013 US guidelines and Spasovski’s 2014 European guidelines.” Take a look at figure 1 in the supplement. Give yourself more than a few minutes…it’s a lot.

The intervention worked, but only modestly.

The mean increase in serum sodium during the treatment period was:
• 10.0 mmol/L (±5.6) in the intervention group
• 8.7 mmol/L (±5.6) in the control group

Normal sodium levels (135–145 mmol/L) were achieved in:
• 60% of the intervention arm
• 46% of the control arm

Editorial side bar: It is depressing that the most current guidelines have not been updated for over a decade and fail to correct the sodium in 40% of patients…What are we doing here?

Back to the study: So yes, sodium moved more with the protocolized care. But the difference was modest.

And clinically? The primary outcome, death or rehospitalization at 30 days, occurred in:
• 20% of the intervention group
• 22% of the control group
• P = 0.45


Little separation, no signal. The authors essentially randomized patients to either standard care or a protocol that essentially looked a lot like standard of care. We should not be surprised that there was not separation. If we want to get separation it is time to move on from being afraid of rapid correction in low risk patients and crack the whip.

After decades of observational data linking hyponatremia to poor outcomes, HIT delivers a sobering message: correcting the number does not correct the prognosis. Or it is just a type 2 error due to the lack of separation between groups.

So the belle of the ball at last year’s Kidney Week was the PISCES trial, which reported a striking ~50% reduction in cardiovascular outcomes with fish oil in hemodialysis patients. That is an extraordinary signal. If you’re unaware, or skeptical, I suggest ’d strongly encourage you to check out NephJC’s coverage or listen to the Freely Filtered episode. The data look clean, internally consistent, and genuinely impressive.

One of the practical sticking points, however, has been how to translate PISCES into practice. Specifically: what fish oil actually matches the intervention used in the trial? The investigators are working with their supplier to bring the study formulation to market, but in the meantime clinicians are left asking what, if anything, can reasonably substitute.

Earlier this year, I was invited to the Medical University of South Carolina to give grand rounds, and during the discussion Ruth Campbell mentioned that she has been using the FDA-regulated, prescription omega-3 product Lovaza for her patients. As it turns out, that choice is quite defensible: Lovaza is fairly similar to the fish oil used in PISCES, both in formulation (omega-3 ethyl esters) and dose, differing mainly in the EPA:DHA ratio:

Because Lovaza is an FDA-approved prescription drug, it fits cleanly into most EHR workflows, and patients are far more likely to receive what the label says they’re getting than with unregulated over-the-counter fish oil supplements. That reliability matters when you’re trying to reproduce a trial signal as strong as PISCES.

I like it. I’ve started prescribing it.

What are you using for your patients?

Last week Apple launched their Hypertension Notification Feature (HTNF) on Apple Watch Series 9 or later and Apple Watch Ultra 2 or later (excluding Apple Watch SE). According to Apple the feature is intended for people over 22 years of age who have not been diagnosed with hypertension. It is not intended to be used during pregnancy. The watch uses photoplethysmography (PPG) which is a 14 letter word (44 Scrabble points) which means that the watch looks at blood volume changes through the skin and uses that information to predict who has hypertension. The watch records 60-second segments of PPG signals as inputs. These signals are collected roughly every two hours throughout discreet 30-day evaluation windows. The watch uses the accelerometer to assure that only PPG signals collecting during rest are used are used to assess for hypertension. A blood pressure score is created for each segment. Segments scored during sleep are ignored. While creating the model, the actual blood pressure was assessed by home blood pressure measurement.

Apple’s white paper about the system provides a classic Table 1 of demographic information on training, validation, and testing cohorts:

I was not familiar The Fitzpatrick Scale. It is an assessment of skin color, V and VI are described by Wikipedia as “dark or brown” and “very dark or black” respectively. Pulse oximetry over estimates oxygen saturation in people with darker skin. Apple prospectively assessed hypertension detection for similar problems.

When determining who to alert for hypertension Apple decided to value specificity over sensitiviy to minimize false positives. From the white paper:

A receiver operating characteristic (ROC) curve was generated based on thedevelopment data, and an operating point was selected to prioritize high specificity — minimizing false positives — while also notifying a significant portion of people with hypertension

After the system was complete, Apple did an additional clinical validation study. They enrolled 2,229 people from two cohorts, all-comers without known hypertension risk factors and those at risk of hypertension based on historical blood pressure values and other risk factors. Each person was sent an Omron Evolv Wireless BP cuff (which scored very high in this review) and instructed to measure their blood pressure twice a day as well as wear the Apple Watch at least 12 hours a day.

Blood pressures were scored using the 2017 ACC/AHA hypetension guidelines:

The cohort for this part of the study was admirably diverse

The full set analysis is the original cohort. The Notification Analysis set only includes people who performed the home blood pressure assessments and wore the watch as instructed. They look reasonably similar except for the higher fraction of women in the Notification Analysis Set.

The investigators found that roughly a third of the Notification Set had hypertension and the watch notified about 40% of them. Only 99 of the 1,278 people without hypertension were given notices that they may have hypertension.

Here is how the test performed using a two-way table:

I feel a little bit out of my element since this is a test being being done in the background on people with no pre-test suspicion of disease. This is unlike any test I have ever ordered or really thought about. It is not a screening situation, where you want to maximize sensitivity at the expense of specificity in order to move a disease enriched population to more specific downstream studies. I think Apple’s description for their rational for tuning the ROC curves is appropriate. They want to capture people with hypertension while minimizing any unnecessary alarm and inconvenience for their customers with false positives.

The FDA application includes information from a 2-year study that is not further described. But it describes that specificity remains high month after month and that almost all of the false positives occur only in the first month.

I am curious, but the data is not provided, if the Hypertension Detection System increases sensitivity over the two years? Does it pick up additional cases of true positives? That would be cool if it did.

If you want to turn hypertension detection on for your Apple Watch, go into the Health App and scroll down to hypertension detection and answer the two questions and then follow through the four panels which describe how it works and to do home BP monitoring for more accurate diagnosis and then a generic warning that hypertension is not a heart attack. The last panel is not from the onboarding flow, but is another panel about hypertension that the health app provides. Nice.

I have hypertension, but I want to play with the warning system so I lied during set up regarding this diagnosis.

Apple received FDA approval for Hypertension Detection. You can read the regulatory filing and response here.

I love getting e-mails from interesting people. Here is a recent one:

Dear Dr. Topf:

First of all, congratulation to your recent promotion!

I have one question regarding the treatment of acute hyperkalemia. As an avid follower of your posts and blogs, I have implemented your “bag of saline with furosemide”-approach for several years in appropriate patients and it works like a charm. I particularly like the beauty of the physiology behind this supposedly simple regime, with flow-induced recruitment of BK (FIKS) supporting the job of ROMK.

However, in my experience, this treatment is woefully underused in clinical practice and little known – even among nephrologists.

Are you aware of a publication substantiating its use? Which reference should I quote?

Looking forward to your reply!

Best wishes,

XXXXXXXXXX

Hmm? Data to support the use of loop diuretics in the treatment of hyperkalemia. Let’s see what we can find.

The first reference I found was this article from 1984

These authors looked at renal potassium excretion in patients following 40 mg of furosemide daily for three days. They did this experiment in 6 health volunteers five separate protocols:

1. Furosemide with a high salt diet (270 mEq of Na per day)
2. Furosemide with a low salt diet (15-20 mEq of Na per day)
3. Furosemide with a high salt diet and captopril, intended to prevent increased aldosterone release with diuresis
4. high salt diet and captopril, this time without furosemide
5. Furosemide with a high salt diet and water load, this was intended to suppress ADH, which has a kaliuretic effect

The authors found that in the acute phase, the first 3 hours after IV furosemide, patients excreted 16 mEq of additional potassium over baseline potassium excretion with the high sodium diet, 19 mEq over baseline in the low salt group (presumably due to higher aldosterone) and 13.5 mEq in the high salt and captopril group.

Interestingly, the authors found that following this acute phase of increased potassium excretion there was a compensatory period decreased potassium excretion in the high sodium group that resulted in just about neutral potassium balance.

It makes me wonder if adding fludrocortisone would be helpful to the “bag of saline with furosemide”-approach to hyperkalemia.

I posed this question to my favorite potassium expert, Melanie Hoenig, and she suggested these references.

First was a circulation manuscript from when furosemide was the new kid and we were still trying to feel it out. These authors were playing around with weekly infusions of furosemide to treat hypertension. And it worked. (Link)

But, helpfully, they also provided information on potassium excretion, but unhelpfully they provided the data in micro Equivalents of potassium per minute.

So we have to do the math

Let’s say:

188 µEq/min from 0 to 22 minutes = 4.1 mEq
180 µEq/min from 22 to 45 minutes = 4.1 mEq
122 µEq/min from 45 to 90 minutes = 5.5 mEq
62 µEq/min from 90 to 120 minutes = 1.9 mEq

So a total of 15.6 mEq in the first two hours with an average of 63 mg of furosemide

195 µEq/min from 0 to 22 minutes = 4.3 mEq
201 µEq/min from 22 to 45 minutes = 4.6 mEq
166 µEq/min from 45 to 90 minutes = 7.5 mEq
91 µEq/min from 90 to 120 minutes = 2.7 mEq

And 19.1 mEq in the first two hours with an average of 210 mg of furosemide for you cowboys.

The next reference she sent was from the Canadian Medical Association Journal in 1968 where they took 115 male students and gave them one of three diuretics:

Hydrochlothiazide 50mg
Hydrochlorothiazide/triamterene 50/25
Furosemide 40 mg

And then tracked them for 24 hours. The results are interesting. Here are the potassium results:

73 mEq of potassium. Pretty impressive. But look how hydrochlorothiazide does just as well, though it is backloaded with most of the kaliuresis coming later in the monitoring period. Hydrochlorothiazide actually resulted in more sodium excretion, over 24 hours than a single dose of furosemide.

The last reference she sent was a 1964 manuscript from Circulation where the authors were playing with the, then novel furosemide. They were using it in edematous patients resistant to available diuretics (acetazolamide, spironolactone, meralluride, and thiazides) as well as normal patients. Here are the daily electrolyte losses with various doses of oral furosemide, from 50 to 600(!) mg.

Good to know that doses beyond 100 mg don’t seem to add much kaliuresis.

So to answer the question, a slug of furosemide seems to be good for 15 mEq of potassium removal acutely, given that the extracellular volume of 70 kg man is about 17 liters, this should drop the serum potassium by a little less than 1 mEq/L.

None of these studies look at patients with hyperkalemia, so I would really like to see any experimental evidence with that, so if you know of any, hit me up on socials.

In 2012, something unusual happened. For the first time since 1868, the year the Detroit Medical College (the future Wayne State University School of Medicine) was founded, a new medical school was opening in the Detroit area. Detroit would no longer hold the distinction of being the largest American city with only a single medical school.

As Oakland University William Beaumont School of Medicine assembled its inaugural faculty, academic appointments materialized from thin air. I was handed the title of Assistant Clinical Professor of Medicine. It felt like a gift.

Over the years, though, that “assistant” began to weigh heavily on me. By 2024, I committed to upgrading that qualifier and pursue promotion. I had no idea just how arduous the process would be. My promotion packet eventually included:

• A five-page Achievements in Service letter
• A 100-page Achievements in Education dossier, anchored by an eight-page letter and 92 pages of artifacts
• A 37-page Achievements in Scholarship document, with a 13-page letter and 24 pages of supporting materials
• A two-page Achievements in Patient Care letter
• A three-page Personal Statement
• My CV
• And a list of a dozen associate professors and professors across North America willing to review and score my work

In July of 2024, I submitted well over 150 pages of narrative, documentation, and supporting evidence to OUWB’s Promotion and Tenure Committee.

A few weeks ago, I received the news I had been hoping for: my promotion was granted. As of July 1, I am officially an Associate Professor of Medicine.

It feels good. More than that, it feels validating. I am grateful that Oakland University viewed my work in social media and medical education not as a novelty, but as serious, productive scholarly activity worthy of recognition.

Hi Dr. Topf,

I hope you are well. I have a clarification question regarding milk alkali syndrome. In this disease mechanism, since you have a loop diuretic like effect on the NKCC2 transport proteins, will you have both hypercalcemia AND hypercalciuria? 

Best,

XXXXXXXX
MS2 

This question asks about the urine calcium level and yes in this conditionyou will have both hypercalcemia and hypercalciuria.

The elevated calcium binds the calcium sensing receptor on the basal lateral side of the thick ascendig loop of Henle tubule cell. This signals a decrease in activity of the ROM-K channel on the apical side of the tubular epithelial cell.

The Na-K-2 Cl channel (NKCC) of the thick ascending limb depends on ROM-K to allow potassium to be recycled. Sodium and chloride are found at way higher concentrations in the tubular fluid than potassium, so without recycling the potassium, the NKCC would grind to a halt for want of K. Since the K that is reabsorbed by the NKCC is able to leave the cell via ROM-K there is always plenty of K available to keep the NKCC turning. It does however make the seemingly electroneutral NKCC (2 cations and 2 anions) become electrogenic, because the potassium just leaks out down its concentration gradient so there is only 1 net cation reabsorbed compared to 2 anions. This makes the tubule electropositive and provides the energy to drive the paracellular reabsorption of magnesium and calcium (and probably some sodium as well).

Following the Ca sensing receptor shuting down ROM-K, the NKCC slows for want of K, and the tubule loses its positive charge. This prevents calcium and Mg reabsorption leading to increased urinary calcium as well as loss of Na in the urine.

Note that this is an appropriate change in calcium handling to help restore a normal calcium level. The high calcium itself shuts down calcium reabsorption. However this is inadequate to normalize calcium in milk-alkali syndrome since the acute kidney injury lowers the GFR so far that not enough calcium escapes to normalize the serum calcium.