NephMadness 2014: Electrolytes Bracket

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PastedGraphic-6This is a highly charged bracket of teams all trying to balance, bind, or buffer their way to the title. For those fans that miss the science lessons in “Breaking Bad” there are representative teams from all parts of the periodic table in addition to organic and inorganic synthetically derivative molecules and mathematical formulas. Arch rivals in the treatment of acute hyponatremia, Hypertonic Saline and Vaptans square off in a first-round osmotic demyelinating showdown of epic tonicity! As if that wasn’t enough osmoles for one round, there is the battle of the Gaps, a duel of K+ sequestrants and topped off by a bicarbonate battle that will go likely down to the last proton. Let’s get ready to rumble!

Selection committee member for the Electrolytes Bracket:

rondonberriosHelbert Rondon, MD
Assistant Professor of Medicine, Renal-Electrolyte Division
University of Pittsburgh School of Medicine
eAJKD Contributor

Dr. Rondon is the associate program director for the nephrology training program at the University of Pittsburgh School of Medicine. He is developing and employing innovative teaching strategies to aid in nephrology fellow education. Specifically his group is developing virtual patient simulation coupled with a space education curriculum to teach electrolyte disorders. His group is also in the process of implementing a kidney biopsy simulation training module to increase procedural skills. Dr. Rondon is exploring the role of eNaC in sodium retention during nephrotic syndrome.

Meet the competitors for the Electrolyte Bracket!

(1) Hypertonic Saline versus (8) Vaptans
Hypertonic Saline

Hypertonic saline is usually administered as 3% NaCl (513 mEq/L of Na & Cl or 1026 mOsm/L) whereas ‘normal’ saline is obviously 0.9% NaCl (154 mEq/L of Na & Cl or 308 mOsm/L). Hypertonic saline as 1.8% & 5% is also available, but its teammate 3% gets the hype so I will concentrate on this. Hypertonic saline is useful in SIADH, a condition with a relatively fixed urine osmolality with urine volume varying depending on solute load. This is because response to Na handling by aldosterone is normal but water handling (ADH effect) is abnormal. This leads to a situation where the serum sodium will only rise if the electrolyte content of the administered fluid exceeds the urine electrolyte concentration.

Let us say a patient with SIADH has a urine Na of 150mEq/L and urine K of 70mEq/L (urine cations = 220mEq/L).

  • The patient is slowly given 500 mL of 3% NaCl (257 mEq of Na).
  • As the urine osmolality is ‘fixed’, these 257 mEq will be excreted in 1.17 L of urine (257/V = 220 → V = 257/220 →  V = 1.17 L, ie, net free water loss of 1.17 L – 0.5 L = 0.67 L or 670 mL.
  • This is what accounts for the Na rise, despite all the Na being excreted.
  • This also explains why hypertonic saline’s teammate, isotonic saline, will never beat an opponent like SIADH.
  • If 500 mL of 0.9% NaCl (77 mEq of Na) were given instead, the sodium would again be excreted but in 350 mL of urine (77/V = 220 → V = 77/220 → V  =  0.35 L,  i.e. leading to a net retention of 0.5 L – 0.35 L = 0.15 L or 150 mL of free water, exacerbating  hyponatremia!

Hypertonic saline is particularly indicated in cases of  moderate to severely symptomatic hyponatremia (eg, seizures), usually acute but also severe chronic (Na < 120 mEq/L), as it is the only method to rapidly increase the serum sodium. Only small increases in sodium (2 – 6 mEq/L) are usually necessary to abort seizures. It is suggested that in marathon runners who become unwell with probable hyponatremia, a bolus of 100 mL of 3% NaCl should be administered in the field (predicted to rise serum sodium by 2 mEq/L) and this could be repeated up to 2 more times 10 min apart if symptoms continue.

Potential drawbacks of hypertonic saline again relate to the risk of over-rapid correction of sodium with potential for osmotic demyelination. For acute hyponatremia, the goal should be to stop life-threatening symptoms with a suggested rise in serum Na of 6 mEq/L in the first 6 hours and postpone any further correction for next day (Rule of Sixes). It should be noted, however, that in cases of acute hyponatremia (present for < 48 hours), the risk for demyelination appears to be less, as full brain adaptation has not yet occurred. Hypertonic saline is a veteran team that plays an aggressive game and frequently intimidates opponents. Their early match-up with team Vaptan is possibly the pick of the first round. We can’t call it!


The hyponatremia matchup is a perennial contest often full of controversy. Just to set the stage, hyponatremia is one of the most commonly encountered diagnoses made in medicine. Obviously, a lot of interest will be brewing for this one. The vaptan team, led by the big man tolvaptan, is no longer the new kid on the block and has accumulated experience over the past number of years. Hypertonic saline, the dinosaur of the conference, continues to stay relevant and will not be intimidated by the tricky opposition.

Vasopressin (ADH) has multiple receptors which mediate its vasoconstrictive (V1a), ACTH release (V1b) and antidiuretic effects at the distal nephron (V2). ADH antagonists that are licensed in the US include the intravenous preparation conivaptan, an inhibitor of V1a and V2 receptors, and tolvaptan, an oral selective V2 antagonist. Vaptans are licensed for short-term in-hospital treatment of hyponatremia and will work when excess ADH is implicated, ie, SIADH (inappropriate) and heart failure or cirrhosis (appropriate ADH release). Inhibition of V2 will cause a water diuresis although subsequent thirst stimulation may limit the rise in serum sodium. Efficacy of tolvaptan was demonstrated by 2 combined trials (SALT 1 & 2) including 448 patients with a combination of SIADH, cirrhosis and heart failure and mean serum sodium 129mE/L. Compared to the placebo group, the tolvaptan group had a 4-5 mEq/L higher sodium level at day 4 & 30.

New team members have so far been redshirted, with lixivaptan failing to get an outpatient license granted despite proving efficacy, mozavaptan only granted license in the Japanese league and satavaptan not yet approved either. Preseason controversy regarding tolvaptan centered on its failure to achieve FDA approval for use in ADPKD despite results from the TEMPO 3:4 trial which demonstrated a slower increase in kidney volume and better GFR compared to placebo. There are some concerns for fans of Team Vaptan. TEMPO 3:4 reported abnormal liver enzymes more commonly in the tolvaptan group, although it must be noted that doses used were much higher than the hyponatremia dose. Also, liver enzymes settled with cessation of the drug. Another concern is that over rapid correction of sodium may occur, potentially leading to osmotic demyelination syndrome, so close monitoring of sodium correction is necessary. In the SALT trials, 1.8% of patients corrected by > 12mEq/L/day (now suggested  ≤ 10 mEq/L and ≤ 8 mEq/L for patients at high risk). If this is a concern, some clinicians (including this one) have started at a lower than licensed dose, 7.5 mg daily. Despite being a young squad, the big-money Team Vaptan have the swagger of conference veterans and will be confident of a successful run to the latter stages of this year’s NephMadness tournament.

(3) Serum Anion Gap versus (6) Urine Anion Gap

Anion Gap (AG): the difference between the measured cations (positively charged ions) and the measured anions (negatively charged ions) can be very helpful in acid/base disorders. This matchup sees the heavyweight serum AG go up against its lesser-known rival, the urine AG.

Serum Anion Gap

Serum Anion Gap (SAG) (in mEq/L) = Na – (Cl + HCO3).

The SAG is arguably the most used biochemical calculation in nephrology. It provides the user with a reflection of unmeasured anions, and hence unmeasured organic acids. The normal AG is mainly due to negatively charged proteins (albumin) and unmeasured acids. SAG is traditionally used in cases of metabolic acidosis, which can be divided into high gap (additional unmeasured organic acids) or normal/low gap (often due to bicarbonate loss). While the entire conference is aware of the strengths of the SAG in cases of high gap (see MUDPILES or the most updated mnemonic GOLD MARK) even in the context of a normal pH (SAG > 20 mEq/L is highly predictive of an underlying  AG metabolic acidosis), the hidden strength of this team is its non-gap utility. Non gap acidoses may be due to HCl precursors gain (TPN, Cl-rich IV fluids), decreased NH4+ excretion (RTA I & IV, Fanconi syndrome, renal insufficiency),  or bicarbonate/bicarbonate precursors loss, either from the gut (diarrhea, GI fistula or ostomy) or from the kidney (RTA II, post-hypocapnia, treatment of DKA). Causes of low AG, without acidosis, may also confuse opponents and is often due to hypoalbuminemia, where the expected normal values for the SAG should be adjusted downward (2.5 meq/L for every 1 g/dL reduction in the serum albumin below 4g/dL). Other causes include elevated cations (lithium, severe hyperkalemia, rarely hypercalcemia and hypermagnesemia, IgG paraproteins). Note that for this to occur, the increase in the unmeasured cation must be accompanied by a measured anion, eg, with Cl or HCO3. We must also watch out for lab error which may underestimate Na in severe hypernatremia (Na+ > 170 mEq/L) and hyperviscosity, or overestimate chloride in severe hyperlipidemia or bromide intoxication (ie, pyridostigmine bromide used in myasthenia gravis). SAG enters this contest with a heavy reputation amongst fans but a somewhat stagnant line-up, with few recent recruits. It is a team full of big men who could be caught out by more mobile opponents.

Urine Anion Gap

Urine Anion Gap (UAG) (in mEq/L) = Na + K – Cl

In healthy people, the UAG is positive (between 20 and 90) as more Na & K is absorbed from the GI tract than chloride. In metabolic acidosis, urinary acidification should occur via NH4+ excretion, in combination with chloride leading to a high urine chloride.

NH3 + H+ ↔ NH4+; NH4+ + Cl-↔ NH4Cl

Therefore, UAG is used as a surrogate for NH4+ and will be negative if urine acidification is normal in the context of a systemic acidosis. This is the case in diarrhea associated acidosis or Type 2 RTA in steady state (not undergoing active treatment  with NaHCO3) where distal acidification remains normal. Conversely, a positive UAG in the face of systemic acidosis suggests inappropriately low NH4+ production and therefore impaired urinary acidification. This occurs classically in cases of

  • type I RTA but also in type 2 RTA  not on steady state (undergoing active treatment with NaHCO3 in which spilling of HCO3 in urine is accompanied by increase in urine Na+)
  • Fanconi syndrome (proximal tubular dysfunction impairs ability to form NH3 from glutamine)
  • type 4 RTA (hyperkalemia  inhibits NH3 production in proximal tubule).

A weakness of the UAG is its utility as most cases of metabolic acidosis can be figured out with history, serum K and urine pH assessment. Another drawback is that non-chloride anions are not accounted for. These anions include ketoacids, bicarbonate or hippuric acid (toluene/glue sniffing). They may be excreted with Na+ or K+ (contributing to a positive UAG as Na+ or K+ are measured but anion are not) or with NH4+ (unchanged UAG as both anion and cation are unmeasured). In these cases, the urine osmolal gap (UAG rival, did not make it to the tourney this year) may be useful to estimate NH4+ excretion as all NH4+ salts are accounted for by the urine osmolal gap. Despite this, the UAG does remain a useful tool in a physician’s armamentarium in assessment of non gap metabolic acidosis. The urine AG will relish this contest against its more famous neighbor, despite the obvious weakness in their line-up. UAG has had a quiet but productive early season, has kept under the radar and will be well up for this potentially giant-killing contest against their more celebrated rivals.

(4) Kayexalate versus (5) ZS-9 (novel potassium binder)

Hyperkalemia —  this is a battle of old versus new. The old guard kayexalate — hardly studied but widely used — and the new guard ZS-9, now rigorously studied but never used.


Kayexalate is the trade name for the drug sodium polystyrene sulfonate (SPS). This is a popular drug given around the world for hyperkalemia. It is an ion-exchange resin designed to exchange sodium for potassium in the colon. However, some degree of calcium is also exchanged. SPS was first reported in Lancet in 1953 and approved by the US FDA in 1958 as a treatment for hyperkalemia. This was 4 years before the FDA required drug manufacturers, as directed by the Kefauver-Harris Drug Amendments, to prove the effectiveness and safety of drugs submitted for indication and approval. This amendment, was a reaction to the thalidomide tragedy in which thousands of children were born with birth defects after taking thalidomide for pregnancy-associated nausea.

So, lets take a look at the data in regards to SPS. The theory is that the resins reactive sulfonic group, which is preloaded with sodium, exchange the bound cation with a cation in the colon (in this case potassium). The original reports from the 1953 Lancet paper demonstrated a hypokalemic effect of the resin in 4 patients with renal failure and 1 healthy volunteer. Sherr et al reported in the NEJM in 1961 the largest clinical data in regards to kayexalate. This uncontrolled study showed serum potassium lowering in a majority of the 30 patients treated with kayexalate having hyperkalemia and acute or chronic kidney failure. Based on this and several other case series the FDA continued to label the product at “effective”.

However, it was recognized that severe constipation was a significant side effect of kayexalate. This lead to the desire to speed the delivery of kayexalate to the colon by the addition of osmotic laxative sorbitol. On the basis of a preliminary study published in the NEJM with 10 patients with oliguria and hyperkalemia the combination of kayexalate and sorbitol was effective at lowering potassium. By 1981, a convenient prepackaged kayexalate and sorbitol suspension gained wide popularity in the US. However, a study published in 1998 which included 6 patients with ESRD with normal or mildly  elevated serum K+ found that the serum K+ rose slightly (0.4 mEq/L) on placebo and did not change during the course of 12 hours in response to a single dose of 30 g of SPS in water, 30 g of SPS in 60 g of sorbitol, or 60 g of sorbitol alone. Also, the FDA had started to receive reports of the combination of sorbitol and kayexalate causing severe bowel injuries such as bowel infarction and ischemia. In 2005, the concomitant use of sorbitol was removed from the FDA-approved labeling. However, the largest maker of the combination agent continued to package this albeit as a lower sorbitol concentration of 33%. In 2009, the FDA issued a Warning of intestinal necrosis with the combination of kayexalate with sorbitol. The popularity of kayexalate has waned in recent years, but its continued use despite a paucity of data regarding efficacy and numerous side effects (others are magnesium and calcium binding).

ZS-9 (Novel Potassium Binder)

ZS-9 was unveiled at ASN Kidney Week 2013 in Atlanta during the late-breaking clinical trials session. This was a surprise indeed for many in attendance, as we are in desperate need for better pharmacologic therapy for hyperkalemia. The study is still not published so we have limited information to share about the drug. ZS-9 is a novel investigational treatment for hyperkalemia. ZS-9 is an inorganic cation exchanger (zirconium silicate) with a high selectivity for potassium. According to the company (ZS Pharma), the drug can bind 9 times as much potassium as sodium polystyrene sulfonate. ZS-9 reported preliminary results of a phase III trial and results of a phase II safety and tolerability study. The phase II study looked at 3 doses of ZS-9 (0.3 g, 3 g, and 10 g) and placebo in 90 patients with mild-to-moderate CKD and hyperkalemia. Both the 3 g and 10 g doses lowered serum potassium as compared to placebo. No hypokalemia, hypocalcemia or hypomagnesemia was noted. Mild constipation was seen in the 3 g dose and vomiting with the 10 g dose. They reported that no discontinuation or serious adverse event occurred. The acute portion phase III randomized placebo controlled trial enrolled 753 patients with hyperkalemia; some with CKD and others with normal kidney function. The phase III trial tested 4 doses of ZS-9 (1.25g, 2.5g, 5g and 10g) or placebo. The primary endpoint was change in serum potassium level over 48 hours. This was met at the 2.5g (-0.46 mEq/L), 5g (-0.54 mEq/L), and 10g  (-0.73 mEq/L) doses. Adverse events were minimal and similar to placebo. The chronic portion of the phase III clinical trial were released by the company in January 2014. This tested the same 4 doses of ZS-9 and placebo as the acute portion but for 12-days. Both the 5 g and 10 g doses lowered serum potassium and had similar side effects as placebo. The company intends to present their results at a national meeting in 2014. This is not the only new potassium binder in development. The company Relypsa is developing a potassium binding polymer RLY5016. This has shown some success in hyperkalemia in conjunction with heart failure.

ZS-9 comes to NephMadness with a lot of hype. However, the drug is untested in the real world and we still await a full peer-reviewed publication. Should be an interesting matchup in an area of medicine with a true need for innovation.

These issues make it difficult to pull for kayexalate during the NephMadness tournament. However, kayexalate has been widely used for years. The matchup between ZS-9 and kayexalate should be a good one.

(7) Bicarbonate in CKD versus (2) Bicarbonate in Acute Metabolic Acidosis

Acidosis RX — this portion of the electrolytes bracket pits two almost identical but actually completely different foes. Bicarb for anion gap acidosis is the perennial favorite, but if you dig deeper you see a real identity crisis. Bicarb for acidosis in CKD is gaining popularity and is a favorite to go deep in the tourney. Should be an interesting battle.

Bicarbonate in CKD

Metabolic acidosis is seen in 30-50% of patients with an eGFR of less than 30 ml/min/1.73 m2. In recent years treatment of metabolic acidosis with sodium bicarbonate has gained more attention. Chronic metabolic acidosis is associated with bone disease, muscle protein catabolism, and some studies have linked metabolic acidosis to progressive glomerular filtration (GFR) loss. As such, the KDOQI guidelines have recommended to keep serum bicarbonate level > 22 mEq/L. What are reasons to be vigilant about treated metabolic acidosis in CKD? It has been shown that muscle wasting is a direct consequence of metabolic acidosis from CKD by impairing insulin signaling, leading to muscle protein breakdown. This leads to a negative nitrogen balance with decreased albumin synthesis. Evidence exists showing that correction of acidosis in CKD ameliorates this catabolic factor. Chronic metabolic acidosis stimulates large production of NH4+ with the aims of excrete the acid load and experimental evidence suggest that NH4+ can activate the alternative pathway of complement causing inflammation and ultimately fibrosis. We have few treatments in our armamentarium to slow the progression of CKD so if simply correcting metabolic acidosis can achieve this important goal, then why not. In an important study de Brito-Ashurst et al randomly assigned 134 patients with CKD (CrCl 15-30ml/min) and serum bicarbonate of 16-20 mEq/L to either sodium bicarbonate (goal >23 mEq/L bicarb) or usual care. The bicarb group had a slower decline of kidney function and number of patient advancing to ESRD over the 2 year study. Two other studies have shown similar results with alkali treatment.

Its clear that treating metabolic acidosis in CKD has grown in popularity and data is coming in to back up this treatment strategy. Most exciting is the data showing a slower loss of kidney function with successful correction of acidosis. Some physicians have expressed concerns regarding the sodium load that accompanies the use of bicarbonate but this concern is unjustified since evidence suggest that the kidneys handle NaCl in a different way then how NaHCO3 is handled and therefore the use of NaHCO3 does not lead to as much hypertension or ECF volume overload as NaCl. This makes bicarb in CKD a threat to go the distance in NephMadness. However, the studies are quite small and more data is needed before we can call them a contender of the whole tournament.

Bicarbonate in Acute Metabolic Acidosis

The use of bicarbonate in the setting of high anion gap acidosis is fraught with issues.

Lets begin with lactic acidosis. First, you have to realize that lactate is a metabolizable organic anion that when oxidized will generate bicarbonate. Remember Lactated Ringers solution? Well, same deal here. If the insult, such as tissue ischemia, is corrected then the generated lactate will be oxidized to form bicarbonate. So, if the underlying pathologic process is abated then the acidosis will generally resolve. Two randomized trials have been performed that fail to show a benefit of using bicarbonate in patients with lactic acidosis and a serum pH of >7.1. However, most would recommend (without much evidence) giving sodium bicarbonate when the serum pH drops below 7.1. The concern is that rapid infusion of sodium bicarbonate may increase the pCO2, accelerate the production of lactate, lower the ionized calcium, expand the extracellular space and raise the sodium concentration. For these reasons it is important to ensure that the patient is adequately ventilated before giving IV sodium bicarbonate in patients with severe lactic acidosis.

What about sodium bicarbonate for diabetic ketoacidosis? Several concerns should be noted before giving bicarb in this situation. First, giving an alkali can lead to a rise in pCO2 just as discussed prior. This can result in a paradoxical fall in cerebral pH as CO2 can cross the blood brain barrier leading to neurological deterioration. Second, the addition of an alkali such as bicarbonate may actually slow the rate of recovery of the underlying ketosis possible by augmenting hepatic ketogenesis. Lastly, overzealous alkali administration can lead to post treatment metabolic alkalosis, since the metabolism of ketoacid anions with insulin will result in the generation of bicarbonate and spontaneous correction of the metabolic acidosis. However, some have recommended to give bicarbonate when the arterial pH dips below 7.0 or if severe life-threatening hyperkalemia is present. It must be recognized that there is no significant evidence that supports the use of sodium bicarbonate in the treatment of hyperkalemia. Bicarbonate administration failed to decrease serum K after 1 h and bicarbonate infusion over 4-6h was found to mildly decrease serum potassium in a study. The mechanism of reduction of serum K+ is likely due to increasing distal Na+ delivery and not due to the classic mechanism of H+/K+ exchange. Actually the traditional use of an ampule of hypertonic sodium bicarbonate in the setting of acute hyperkalemia can exacerbate hyperkalemia by causing hypertonicity and driving potassium out of cells by a solvent drag mechanism.

What about a situation where sodium bicarbonate/or another alkali is appropriate in anion gap acidosis? The administration of sodium bicarbonate in the setting of metabolic acidosis in suspected methanol or ethylene glycol intoxication can help in limiting the end-organ accumulation of toxic acids such as formic acid. Then it works by converting the toxic acids to the anion state (formate), which is unable to diffuse across the cell membrane and can be easily excreted in the urine.

This will be an interesting matchup as bicarb in anion gap acidosis is limited its use only in extreme situations (severely acidotic or after toxic ingestion). Whereas, bicarb in CKD can be used at milder forms of acidemia.

-Written and Edited by Matt Sparks, Paul Phelan and Helbert Rondon

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