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Hypertonic Saline versus Vaptans

Winner: Hypertonic Saline

Hypertonic saline squeezes out Team Vaptan with a buzzer beater to sneak into the next round of NephMadness. This was the big matchup in the first round in the Electrolyte region and it didn’t disappoint. The big man Tolvaptan, likely still hurting from its surprise preseason loss to the FDA for approval in APKD, just didn’t deliver. In TEMPO 3:4, despite reaching its primary endpoint by slowing the increase in total kidney volume (& the decline in kidney function) over a 3-year period there were issues. A higher dropout rate (23 v 14%) versus placebo limited its power (and hence P value) and the higher rate of “clinically significant” rises in LFTs ultimately ruined its chances against the FDA (4.95 vs 1.2% for ALT). The veteran Hypertonic saline proved its critics wrong and will fancy its chances to a run deep in NephMadness. Hypertonic saline, as the only agent capable of rapidly increasing the serum sodium, can be a lifesaver. The types of situations where it can be invaluable include precipitous drops in serum sodium associated with primary polydipsia, ingestion of MDMA (“ecstasy”) and exercise-induced hyponatremia, as occurs in marathon runners. The common mechanism here is a marked increase in water intake with failure to adequately suppress ADH. The risk for osmotic demyelination is lower with acute hyponatremia (and risk for cerebral edema due to the low sodium is high) meaning we should not be afraid of using hypertonic saline when indicated. However, it must be noted that such patients may autocorrect quickly, by excreting a dilute urine, when the stimulus for ADH suppression is removed.

Serum Anion Gap versus Urine Anion Gap

Winner: Serum Anion Gap

Hypertonic Saline will now face off against Serum Anion Gap (SAG) who won its local rivalry with Urine Anion Gap by some distance. The hyped “Battle of the Gaps” turned out to be one way traffic as the wealth of physician experience and familiarity with SAG made the difference. In our NephMadness scouting report of SAG, we concentrated on its versatility and application in different situations (high, normal, low gap; acidosis, non-acidosis) which is an obvious strength. It must be noted, however, that sometimes the SAG is an oversimplification. For example, the degree of change in SAG for each unit change in HCO3 is not always uniform, being more with lactate than other anions such as ketoacids. This may be important when using SAG in conjunction with other tools, such as delta HCO3 (expected HCO3 may be different depending on the cause of the acidosis). A nice review of the current use of SAG for nephrologists can be found here. The urine anion gap (UAG) or sometimes referred to as the urine cation gap or the urine net charge. The point of measuring the UAG is to measure the NH4 content in the urine. This is because with hyperchloremic metabolic acidosis, NH4 is excreted in the urine usually with Cl. Thus, urine Cl usually exceed the sum of the urine Na and urine K. This results in the negative UAG. Why? Urine NH4 is difficult to measure so this is a surrogate of NH4 content. The problem with UAG is that when the relationship between urine NH4 and Cl is disrupted then the UAG may be misleading. This is when another unmeasured urinary anion is present (NON-CHLORIDE).
Examples include

• Beta-hydroxyburyrate
• acetoacetate in ketoacidosis
• hippurate following toluene inhalation (glue-huffing)
• bicarbonate with proximal RTA is treated with alkali
• D lactate
• 5-oxoproline (with acetaminophen ingestion)

In these situations it may be better to perform a urine osmolal gap (UOG). This is another indirect measure of urinary NH4 excretion. The difference between the directly measured and the calculated urine osmolality is termed the UOG. Urine osmolality is generally made up of ammonium salts such as NH4Cl and NH4+other anions. Thus, the UOG, in contrast to the UAG, is still useful when unmeasured anions are excreted in the urine. For these reasons UAG just couldn’t keep up with SAG and, unfortunately, their season comes to an end. How with SAG fare against Hypertonic Saline. We shall see.

Kayexalate versus ZS-9 (novel potassium binder)

Winner: ZS-9 (novel potassium binder)

ZS-9 entered the competition with lots of momentum and hype (despite little substance as yet) and wins over Kayexalate, its unloved opponent. ZS-9/zirconium silicate works as an inorganic cation exchanger and has high selectivity for potassium. It appears to be well tolerated in its early studies, with no diarrhea reported. It has a cool name, novel mechanism, and was always going to beat Kayexalate. However, it needs hard data to back it up from here so my prediction is it will struggle from here in this years tourney.

Bicarbonate in CKD versus Bicarbonate in Acute Metabolic Acidosis

Bicarbonate in CKD

Bicarb in CKD beats Bicarb in Anion Gap Acidosis in what was a contest of emerging evidence versus no evidence. Certainly, the idea of treating CKD-associated acidosis with NaHCO3 (or equivalents such as sodium citrate) is gaining traction with exciting evidence suggesting retardation of progressive renal dysfunction. Another approach to this is by using dietary interventions with high fruit and vegetable intake to counteract the systemic acidosis. A recent study has demonstrated this can work over one year in a CKD stage 4 population. A potential worry with this diet is the risk for hyperkalemia although this was not evident in the cited study despite universal ACE inhibitor use. In patients with ESRD, acidosis is generally corrected by their dialysis. Persistent acidosis can be be managed by altering bicarbonate concentration of the dialysate from the standard 35 mEq/L. KDOQI guidelines suggest midweek pre-dialysis bicarb levels >22 mEq/L which is consistent with recent survival data in hemodialysis patients. ZS-9 versus Bicarb in CKD will showcase two up and coming teams but my pick is the team that is slightly more established with more evidence to back up the hype.

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