Paul A. Welling, MD

Dr. Welling is Professor of Physiology and Director of the Maryland Center for Kidney Discovery at the University of Maryland Medical School. He is an authority on the molecular bases of potassium and sodium balance, electrolyte disorders, and hypertension. Follow him @PAWellingMD.

Competitors for the Hyponatremia Region

European Guidelines vs US Guidelines

Cerebral Salt Wasting vs SIADH

Hyponatremia is the most common electrolyte disorder and yet, it is the most misunderstood and arguably the hardest to manage. Understanding its diverse etiologies and treatments requires an intimate familiarity of water balance and extracellular volume physiology. Of course, that’s what makes the concept so attractive. It appeals to the cerebral nature of all nephrologists and provides opportunities to mesmerize your colleagues with your astute knowledge of kidney wonder. With new guidelines, new drugs, and controversies, this topic has a lot to offer. It’s why the winner of the hyponatremia region should go far in the tournament.

In the first matchup, we have two different guidelines for the diagnosis and treatment of hyponatremia. By pitting the “American Guideline” (AG) against the “European Guideline” (EG), this matchup has special drama. At first glance, it may be hard to choose a clear winner. After all, both are strong and expected to score a lot of points. Both are exhaustive, scholarly tomes assembled by leading experts. Both offer many nuggets of wisdom. Both should be considered must-reads for every nephrology fellow and both are must-have references for every personal nephrology library.

As outlined by Hoorn and Zietse, the two guidelines have more similarities than differences:

• both move to fixed bolus treatments of hypertonic saline (3%) for acute or symptomatic hyponatremia;
• both are in near agreement about correction rates, although the AG exercises greater caution for patients at highest risk of osmotic myelinolysis syndrome (OMS) and sets minimum standards for correction; and
• both use similar approaches – desmopressin and free water – to deal with overcorrection.

Copyright: Thomas Pajot / Shutterstock

The guidelines diverge in four important areas. The EG beats the AG on three of these:

• The EG used a quality of evidence scoring, while the AG used a critical evaluation of literature by an expert panel. This gives a basket advantage for EG (2+).
• AG followed the traditional approach of classifying hyponatremia by osmolarity and volume status. EG thoughtfully distilled these concepts into a useful and sensible diagnostic algorithm. EG scores a three pointer (+3) on this one.
• Making a correct diagnosis of volume status is central to appropriate management of hyponatremia. EG relies on the kidneys’ remarkable ability to report water handling (evaluated by urine osmolarity) and precisely measure the effective circulating volume (evaluated by urine sodium), instead of clinical assessments, which are often flawed. Caveats to the approach are incorporated into the EG algorithm, and measurements of the fractional excretion of urate (FEurate) are suggested to support the diagnosis. FEurate > 12% is the most reliable measure of SIADH, regardless of diuretic use. Perhaps, the newer version of EG (updated every 5 years) will include FEurate in the algorithm. EG scores another three-pointer (+3).
• The most contentious difference between the two guidelines relates to the use of vaptans. Both agree that vaptans should not be used in the treatment of acute hyponatremia and are contraindicated in hypovolemic hyponatremia, but the AG uniquely includes vaptans to increase free water clearance in SIADH and hypervolemic hyponatremia. Efficacy of vaptans to raise serum sodium (SNa) in SIADH, heart failure, and liver disease has been demonstrated in large randomized clinical trials (RCT). Careful monitoring of SNa is required, but incidence of ODS may be very low. The downside is that hard outcomes, such as mental status and survival, have not been studied in the same way. Because of the uncertainties about whether the benefits of vaptans outweigh concerns of overcorrection and ODS, the EG recommends against vaptans. In my view, until a head-to-head comparison of vaptans to the much cheaper and potentially safer alternative, urea, are studied in large RCT with safety measures and hard primary endpoints, we will not know for certain. Nevertheless, I give two points to AG on vaptans because the armamentarium of drugs that increase free water clearance is small; vaptans are proven to safely and effectively lower SNa; and based on small studies, vaptans are likely to have hard benefits in SIADH and hypervolemic hyponatremia.

Thus, the European Guidelines team wins a hard-fought game by six points.

The competition between the syndrome of Cerebral Salt Wasting (CSW) and SIADH in the next hyponatremia matchup is more lopsided, analogous to Kansas University playing Northwestern if Northwestern made it to the NCCA basketball tournament (they did once). It is hard not to be seduced by the CSW mystique, and the way it challenges the paradigms of water and salt balance physiology. Nevertheless, CSW should remind us of the infamous aphorism coined by a University of Maryland Medical School legend, Dr. Theodore Woodward, “When you hear hoof beats behind you, don’t expect to see a zebra.”

A careful study of 100 patients with acute hyponatremia and subarachnoid hemorrhage revealed the majority (72%) had syndrome of inappropriate anti-diuresis, and the remainder had glucocorticoid insufficiency (8%), or developed hypovolemia (10%) or were administered incorrect fluids (10%), but there were no cases of CSW. So, don’t expect to make a CSW diagnosis. While hyponatremia commonly develops following subarachnoid hemorrhage, CSW is extraordinarily rare. Instead of rewarding CSW any points, I’ll reserve them for the fellows who cite the Hannon study, and suggest repeated measures of FEurate to differentiate between acute SIADH and CSW when isotonic saline is being used to treat the acute hyponatremia, and recognize “desalination” as a potential hazard in misdiagnosis and mistreatment.

SIADH doesn’t win by default. But, let’s face it. SIADH is highly relevant to the nephrology practice and has become even more intriguing with the advent of copeptin based classification schemes. Understanding how to properly diagnose and treat SIADH is a mainstay of nephrology. Thus, I predict SIADH will win by a landslide in this bracket.

The first-round picks leave us with a battle between SIADH and the European Guidelines. Hyponatremia is so interesting because it has broad origins and disparate management strategies. Thus, SIADH is too narrow to emerge as the winner of this bracket. By contrast, the European Guideline distills all the complexities of hyponatremia into one, easy-to-follow algorithm. Although the algorithm is still wanting for robust RCT evidence, and it may not deal with all the nuances, it is still a winner because it is based on a graded evaluation of the literature, and a sound understanding and translation of the pathophysiology. The logic of the algorithm makes it a wonderful teaching tool. More importantly, the European Guideline is broadly applicable to all types of clinical practice, and implementation of EG should dramatically improve patient care.

Overall, I predict the European Guidelines team will win the Hyponatremia bracket, and go far in subsequent rounds.

– Post by Paul A. Welling. Follow him @PAWellingMD.

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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