#NephMadness 2024: JHM’s Things We Do For No Reason(TM) Region

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Selection Committee Member: Anthony Breu @tony_breu

Anthony C. Breu is the Director of Resident Education at the Veterans Affairs Boston Healthcare System (VABHS) and an Assistant Professor of Medicine at Harvard Medical School. He completed his undergraduate degree in biomedical ethics at Brown University, where he also received his medical degree. Dr. Breu was an internal medicine resident and chief medical resident at Beth Israel Deaconess Medical Center. Since 2013, he has served as a hospitalist and is the director of the medical consult service at VABHS. He is the co-Deputy Editor of the Things We Do For No Reason series in the Journal of Hospital Medicine. Dr. Breu is a proponent of the use of digital education, including Tweetorials, and is the co-host of The Curious Clinicians podcast.

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Selection Committee Member: Farah Daccueil @FarahDaccueil

Farah Daccueil is an Assistant Professor at Stony Brook University Hospital in Long Island, NY. She completed her fellowship at NYU/Winthrop also in LI, NY. At Stony Brook University she serves as the Associate Program Director of nephrology fellowship. Her clinical interest with patient quality improvement, health disparities, and social determinant of health in nephrology.

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Selection Committee Member: Lenny Feldman @DocLennyF

Leonard “Lenny” Feldman is an Associate Professor in Internal Medicine and Pediatrics and a hospitalist in the Division of Hospitalist Medicine at Johns Hopkins University School of Medicine since 2004. He is also an Associate Program Director for the Osler Internal Medicine Residency. Dr. Feldman has focused his research on urban health, resident education, on-line education, and high-value care. Other interests include patient education, consult medicine, evidence-based medicine, and quality improvement. He is the Editor-in-Chief for SHM Consultative and Perioperative Medicine Essentials for Hospitalists and a Deputy Editor for the Journal of Hospital Medicine‘s”Things We Do For No Reason”^TM series.

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Writer: Imran Chaudhri

Imran Chaudhri is a nephrology fellow at Beth Israel Deaconess Medical Center in Boston, MA. He completed his medical training at Stony Brook University Hospital in NY where he was selected as a chief resident. His main interests are medical education, acid base physiology, and genetic kidney diseases.

Competitors for JHM’s Things We Do For No Reason Region^TM

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Image generated by Evan Zeitler using Image Creator from Microsoft Designer, accessed via https://www.bing.com/images/create, January, 2024. After using the tool to generate the image, Zeitler and the NephMadness Executive Team reviewed and take full responsibility for the final graphic image.

As physicians, we always try to do the best for our patients, after all, “do no harm” is in our Oath. Patients with kidney disease often require regular monitoring of their blood work and kidney function.  In our attempts to diagnose and monitor our patients, we often order a plethora of tests which are used to make management decisions.  However, despite our best intentions, sometimes we look for the extra pass or take the unnecessary shot.  This year, we’ve been lucky enough to partner with the Journal of Hospital Medicine’s Things We Do For No Reason™ to look at two teams that may intuitively and physiologically make sense, but have weak evidence: inpatient use of phosphate binders in acute kidney injury, and use of the urine anion gap as part of the evaluation of metabolic acidosis. Hopefully by the end of this write-up you’ll have a million reasons to change your practice! 

Team 1: Inpatient Use of Phosphate Binders in AKI

Many hospitalized patients develop acute kidney injury (AKI) during their stay. As one’s glomerular filtration rate (GFR) acutely decreases, it often leads to serum phosphate elevation. When this occurs, as nephrologists, we are often asked about starting phosphate binders (which bind enteric phosphate) to address the elevated phosphate level. Although there is some evidence for use of phosphate binders in chronic kidney disease (CKD), are we just treating a number in AKI? Let’s dive a little deeper. 

How Do Phosphate Binders Work?

Before touching on any data, how do these medications even work?! Phosphorus can be found in many foods including dairy products and sodas in both organic and inorganic forms. After foods with phosphorus are consumed, intestinal phosphatates break down the organic forms and thus the majority of the phosphorus to be absorbed exists in its pentavalent form combined with oxygen called phosphate (PO43-). This phosphate is then absorbed mainly through a passive concentration dependent method, although some is absorbed via an active process involving 1,25-dihydroxyvitamin D. Phosphate binders are medications that bind up these phosphates leading to less freely available phosphate for absorption. There are multiple phosphate binders on the market, including calcium-containing and non–calcium-containing compounds. These medications are most effective when they are in the gut at the same time as dietary phosphate (ie, after a meal), however the decrease in intraluminal phosphate does upregulate phosphate transporters in the gut, ultimately limiting their effectiveness.

How Does Hyperphosphatemia Develop In CKD?

In patients with CKD, mineral bone disease (MBD) is a consequential yet difficult to treat pathology which ultimately arises from impaired excretion of phosphate due to decreasing glomerular filtration rate. While MBD was initially thought to be a parathyroid hormone (PTH) driven process, the discovery of phosphaturic hormone fibroblast growth factor-23 (FGF-23), whose levels rise before any other laboratory alterations of mineral bone disease, changed our understanding of MBD. As kidney function declines and phosphate continues to rise, decreased synthesis of active 1,25 dihydroxy vitamin D by the kidney leads to increased PTH levels. The culmination of the electrolyte and hormonal changes causes deleterious bone remodeling; however, both phosphate and FGF-23 have also become prime culprits in the excess vascular and cardiac morbidity and mortality and have been associated with poor outcomes. The quality metric recommended by the NKF KDOQI is to keep a calcium-phosphate product (CaxP) < 55 to prevent these poor outcomes.

As the inciting event, limitation of intestinal phosphate absorption, either through dietary adjustments or use of phosphate binders, has become a mainstay of management of MBD despite overall weak evidence to support this practice and lack of a clear target phosphate (with unfortunate recent news of the termination of the largest trial attempting to address a phosphate target). Most studies have found no benefit of one class of phosphate binder over another in treatment of hyperphosphatemia in CKD, but there is some evidence that non-calcium-containing binders, specifically sevelamer may have a mortality benefit over calcium-containing binders. Still, phosphate binders contribute to both increased pill burden (with poor compliance) due to both the size of the pills and dosing frequency and growing medical costs ($1.5 billion in Medicare costs in 2015). 

How Does Hyperphosphatemia develop in AKI?

While the preeminent mechanism in development of hyperphosphatemia mirrors that of CKD ( decreased ability to excrete phosphate through the urine as GFR declines), there are additional mechanisms through which hyperphosphatemia develops in AKI. Conditions that cause massive cell turnover, such as tumor lysis syndrome (TLS), can also cause hyperphosphatemia due to intracellular release of phosphates. This syndrome often also causes AKI, hyperkalemia, hyperuricemia, and hypocalcemia. Hyperphosphatemia increases the overall CaxP (despite the associated decrease in Ca due to precipitation). Uric acid and calcium-phosphate then crystallize in the tubules leading to tubular obstruction which can cause AKI (though recent findings demonstrate that extracellular histone mediated endothelial damage can also lead to AKI). The deterioration in kidney function then leads to worsening clearance of potassium and phosphate which then raises the serum levels further.  Treatment often involves improvement in uric acid with agents such as rasburicase and maintenance of urine output to prevent tubular obstruction and allow for excretion of potassium and phosphate. Finally, cellular shift in the setting of extreme acidosis has been reported to occur in the setting of diabetic ketoacidosis or lactic acidosis, especially given these patients tend to have AKI.

Phosphate Binders in Acute Kidney Injury 

Now that we have given some background on how we approach hyperphosphatemia in CKD and its development in AKI, let’s finally get to the bread and butter of this team: Phosphate Binders in AKI.  Like in CKD, there is no clear target for reduction of phosphate in AKI, but expert opinions suggest treatment when Phosphate is > 10mg/dL (due to risk of sequestration of calcium), and monitoring with low level hyperphosphatemia. Much of the concern for adverse outcomes from hyperphosphatemia stem from extrapolation of CKD (though there is associated mortality increase in FGF23 in AKI), and concern for acute phosphate nephropathy.

In this context, phosphate binders can be used to treat hyperphosphatemia, but there has been no research to demonstrate benefit. Additionally, in many cases, patients have altered oral intake diminishing the purpose of these binders. Often these patients require kidney replacement therapy, and continuous kidney replacement therapy (CKRT) specifically can often cause hypophosphatemia due to improved solute removal over time. In CKRT patients, phosphate binders are often held for this reason, but if continued in error, they can cause dangerously low levels.  There may be some benefit to the long-term use of phosphate binders in these patients if they remain on dialysis over time, but their use in the acute setting is controversial. In alternative mechanisms of hyperphosphatemia, such as TLS, phosphate binders may be used in this context along with dietary restriction of oral phosphate intake (< 1 gram) to limit the effect of oral phosphate intake on serum levels. For patients with severe hyperphosphatemia, kidney replacement therapy allows for definitive clearance of phosphate.

Overall in AKI, phosphate binders likely have little benefit due to their mechanism of action. As described above, these medications bind inorganic phosphate in the gut and prevent absorption. While mouse models have shown some benefit in dietary phosphate restriction, many patients with AKI who develop hyperphosphatemia are critically ill and often on kidney-supportive restricted diets, which restricts dietary phosphate intake to 1 gram or less. Additionally, many of these patients may be on tube feeding regimens that also limit dietary phosphate and may affect overall absorption of phosphate. In these contexts, binders will have a limited role as there will be limited enteral phosphate to bind and prevent absorption of.  This is in contrast to CKD patients who are often not critically ill and have higher dietary phosphate intake, making binders more effective.

Putting aside the potential long-term benefits of phosphate binders, these medications have adverse effects of their own. Phosphate binders confer an additional pill burden on patients who may already have a large amount of required pills. These medications often have to be taken with each meal and can be difficult to swallow due to size. Additionally, due to the limited binding capacity per pill, patients often need to take multiple pills for effectiveness, and patients also complain about the taste of the pills. These binders have also been shown to cause significant GI side effects including nausea, vomiting, diarrhea, constipation, and obstruction. All together, these adverse effects can limit adherence to the medication for patients. The aluminum-containing binders are very effective at reducing phosphate levels though rarely used, as aluminum toxicity can lead to encephalopathy, seizures, bone loss, and lung disease. Lastly, as stated above, these medications can be costly and they contribute to growing medical costs for the health system.

Overall, there is no evidence (either short-term or long-term) to support the use of phosphate binders in inpatients with AKI.  The main contexts in which hyperphosphatemia occurs is AKI and TLS.  Although it  can be dangerous in these situations, the levels often improve with treatment of the underlying condition or with improvement in kidney function. Additionally, these patients often do not have enough dietary phosphate intake to make the use of binders worthwhile. There is some evidence for the use of phosphate binders in CKD, but even then the evidence is limited and not consistent. As these medications cause undue pill burden and impairments to quality of life that likely outweigh any benefit, the inpatient use of phosphate binders in patients with AKI is not recommended.

Team 2: Urine Anion Gap

Switching from phosphate to physiology, we’re going to do a deep dive into the urine anion gap (UAG) – a tool that’s been used for years to assist in the differential diagnosis of normal anion gap metabolic acidosis. Think of the UAG as the grizzled veteran who has had a nice career, but does it really deserve to be in the hall of fame for determining the kidney’s role in acidosis? 

Though the urinary anion gap (UAG = Urine Na + K – Urine Cl) may not garner as much attention as its sibling-from-a-different-equation, the serum anion gap, this year’s NephMadness is trying to change that. We look to the urinary anion gap to answer a simple question: is the kidney increasing acid excretion (as it should) in the setting of acidosis? When the answer is yes, or when the UAG is negative, the kidney is out of the hot seat (ie, there’s no renal tubular acidosis). Interpretation of this answer becomes a bit murkier as we look at how the UAG actually addresses this question. 

First, a word on the nephron’s response to acidosis. In response to metabolic acidosis, the nephron compensates by reabsorbing as well as generating new bicarbonate. Bicarbonate generation is paired with newly generated acid that requires excretion, either through titratable acids (mostly phosphates and occasionally creatinine) or ammonium (NH4+: make note of that positive charge for later). Proximal tubule cells generate ammonium via metabolism of serum derived glutamine. This ammonium then enters the urine via the apical sodium hydrogen exchanger (NHE3) or the H+ ATPase through parallel transport of the proton. Ammonium is reabsorbed in the thick ascending limb via the sodium potassium chloride cotransporter (NKCC2) then binds to anions in the interstitium with higher concentration of anions in the inner medulla to create an interstitial ammonia gradient. Ammonia and H+ are then secreted into the urine in the cortical collecting duct due to this gradient. The end result is that virtually all free hydrogen protons are bound to ammonia as ammonium with the remainder bound to the titratable acids as above. This results in the majority of the excreted acid load being ammonium.

The principle behind the UAG is that under normal physiologic conditions, urinary cations (Na+ and K+) and anions (Cl–) should be equal.  When ammonium is generated and ultimately excreted in the urine, an extra cation has been added to the picture and needs to be excreted with an anion to maintain electroneutrality. Thus, we use the urine chloride concentration and the UAG as a surrogate for measuring urine ammonium. Unfortunately, due to technique, there are a paucity of laboratories which directly measure urine ammonium levels, The urinary anion gap was proposed as a mechanism in the 1980s to estimate the urinary ammonium.

The Clinical Uses for the UAG

Now that we understand how the kidney responds to acidosis, we can discuss how the UAG is used. As above, the UAG is a surrogate for estimating the urinary ammonium concentration. When evaluating patients with normal anion gap metabolic acidosis (NAGMA), the UAG is used to evaluate if distal nephron acidification is intact. If the NAGMA is due to an extrarenal cause (such as diarrhea), the kidney is able to appropriately acidify the urine distally and excrete the acid load mainly as ammonium. Since the ammonium is mainly excreted with chloride, the overall UAG will be negative when the cause of NAGMA does not affect distal nephron acidification. When distal acidification is not intact (such as in Type 1 and Type IV renal tubular acidosis), there will be less urine ammonium and therefore urine chloride and the overall UAG will be positive. Even though the UAG can be helpful in evaluating NAGMA, there are limitations to its use.

Limitations to the Use of the UAG

Like any mathematical equation or model, the UAG has multiple assumptions or conditions which should be met for the result to be valid:

1. No additional anions in the urine
2. Normal kidney function

Let’s go through each one of these assumptions to demonstrate the UAG’s potential shortcomings.

Additional Anions in the Urine

As the UAG is designed to account for the difference in urinary anions and cations, elevated concentrations of additional anions can lead to UAG misinterpretation. If unmeasured anions are present in the urine (like lactate or ketones), they may be excreted with ammonium as its pair anion. Thus, urine chloride levels become an inaccurate surrogate for ammonium excretion. These additional anions may also be excreted with other cations like sodium or potassium. These additional anions can thus “falsely elevate” the UAG. Individuals who ingest toluene generate metabolites (mainly hippuric acid and hippurate, an anion) which are freely excreted into the urine. Individuals with a proximal RTA exhibit bicarbonaturia, especially when treated with alkali therapy. Here, again, we have an additional unmeasured anion in the urine. In all of these cases, our initial assumption that urine chloride reflects ammonium excretion comes into question.

Finally, changes in the dietary intake of sodium or potassium may occur without a paired increase in intake of chloride. Consumption of potassium salts, either from salt substitutes, plant based foods, or additives with sodium paired with non-chloride anions, will introduce additional anions that will be excreted in the urine.

Acute Kidney Injury and Chronic Kidney Disease

In patients with impaired kidney function, ammonium generation is also impaired. Similarly, reabsorption of other anions such as sulfites and organic anions is also impaired (higher concentrations in the urine) and make urine chloride again a poor surrogate of ammonium excretion. In patients with CKD, the UAG does not act as a good indirect measure of urinary ammonium.  If urinary sulfite and phosphate are accounted for in the calculation, the UAG may be a better indirect measurement. Of note, these measurements can be cumbersome and not even possible in some instances.

Overall, the UAG was a good attempt at trying to indirectly measure urinary ammonium, but given the significant limitations, its clinical use is very questionable.  After all, given the poor correlation that the few available studies with direct comparisons to urinary ammonium across varying populations have demonstrated, its utility certainly should be questioned. How can we get around these limitations of estimation? Well, clearly, more direct measurement of urinary ammonium! There has been a significant movement in the nephrology community to petition labs to directly measure urinary ammonium and while it is becoming more common, there remains a large need for more widespread measurement!

From the information presented above, both the use of phosphate binders in AKI and the use of the UAG in metabolic acidosis have clear limitations. While there may still be rare situations where their use is indicated, broad use of phosphate binders in AKI and UAG clearly fall under the Things We Do For No Reason™. Now to decide…which Thing We Do For No Reason™ deserves to move on in this year’s NephMadness? 

– Executive Team Members for this region: Jeff Kott @jrkott27 and Samira Farouk @ssfarouk | Meet the Gamemakers

How to Claim CME and MOC
US-based physicians can earn 1.0 CME credit and 1.0 MOC per region through NKF PERC (detailed instructions here). The CME and MOC activity will expire on May 31, 2024.

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