Dr. Helbert Rondon, @NephroMD, is an Associate Professor of Medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine where he also serves as the Program Director of the Nephrology Fellowship Training Program. Dr. Rondon has authored several publications in the field of hyponatremia. He is an NIH funded clinical investigator. His research focus on the effects of oral urea on the clinical outcomes of chronic hyponatremia and the use of hypertonic saline and desmopressin for slow correction of chronic severe hyponatremia.
Dr. Biruh Workeneh, @bdubNephro, is a nephrologist at the University of Texas MD Anderson Cancer Center and has contributed to a better understanding of the complex relationship between cancer, electrolyte imbalances, and cancer therapy.
AJKDBlog Interviews Editor Timothy Yau (@Maximal_Change) talks to Dr. Helbert Rondon and Dr. Biruh Workeneh about their recently published Review in AJKD on electrolyte and acid-base disorders in patients with cancer.
AJKDBlog: Let’s start with pseudohyponatremia – probably the most well known and most discussed pseudo-electrolyte disorders. Can you explain the different assays using direct and indirect ion selective electrodes (ISE) and how pseudohyponatremia can be seen when there is higher percent of solid phase proteins in plasma?
First, we should start by saying that both methods used the ISE technique where an electrode that includes a membrane selective for sodium ions is submerged into an aliquot of the serum sample to measure sodium ion activity in water (sodium ions only distribute in the water fraction of serum). The ISE electrode produces a potential change due to the exchange of sodium ions on the surface of the electrode membrane and the serum sample. This potential change is then converted into a concentration using the Nernst equation and a result is produced.
Most clinical laboratories routinely measure serum sodium in automated analyzers using the indirect ISE method. In this method an aliquot of the serum sample first undergoes a significant dilution step (typically dilution of 1:16-1:34) prior to sodium measurement. Dilution is needed to extend the life of the electrode and to decrease the volume of serum sample needed for testing. Under normal conditions, plasma is 93% water and 7% solids (proteins and lipids). After measuring sodium ion activity in the post-dilution serum aliquot and converting it into sodium concentration, the analyzer back calculates the serum sodium concentration in the pre-dilution serum aliquot by multiplying the sodium concentration in the post-dilution serum aliquot by the dilution factor used (Figure 1A). In patients with severe hyperproteinemia or hypertriglyceridemia, the solid phase of serum is greater than 7%, and hence the water fraction would be less than 93%. (Figure 1B). Because sodium ions only distribute in the water fraction of serum, the sample with a lower water fraction will contain less sodium ions. If this sample undergoes a significant dilution, the effect of the solids coming from the original sample will be negligible here and the electrode will measure then a lower sodium ion activity in water, and hence a lower sodium concentration. Therefore, indirect ISE methods are affected by the distribution of solutes and water in the sample. This phenomenon is known as the “electrolyte exclusion effect” or “volume displacement effect.”
In contrast, direct ISE methods do not involve a dilution step. Electrodes are submerged in a serum aliquot where sodium ion activity will be measured and then converted to sodium concentration. Since sodium ion activity is measured in the water fraction of an undiluted serum sample, the presence of a lower water fraction (<93%), as it occurs in hyperproteinemia or hypertriglyceridemia, will not affect the results. Sodium concentration measured in serum water is expected to be higher than in total serum. To standardize the results with sodium concentration obtained by indirect ISE, sodium concentration in water serum is multiplied by 0.93 to transform the results to sodium concentration in total serum (Figure 2). Sodium concentration using direct ISE methods tends to be 2 mmol/L lower than the one obtained with indirect ISE methods.
AJKDBlog: If this is suspected in diseases such as paraprotein diseases, hypertriglyceridemia, or lymphoproliferative diseases, how can clinicians confirm a true plasma sodium with direct ISE measurements?
In cases where isoosmolar hyponatremia is encountered, clinicians frequently order serum protein electrophoresis and/or lipid profile to rule out common abnormalities leading to pseudohyponatremia. However, isoosmolar hyponatremia is more commonly associated with the presence of ineffective osmoles such as urea or ethanol in the setting of hypotonic hyponatremia (e.g., hyponatremia in ESKD, beer potomania). Therefore, the easiest and most efficient way to confirm pseudohyponatremia is to simply order a whole blood sodium measured in a blood gas analyzer or point-of-care device (i.e., iSTAT).
AJKDBlog: You also discuss a less well-known phenomenon that has a very similar mechanism – pseudohypobicarbonatemia. It sounds like this is very similar to pseudohyponatremia that can be seen with indirect ISE measurement. Would this also impact other values in the chemistry panel such as BUN, Cr, and calcium, or are these measured differently in laboratories?
Pseudohypobicarbonatemia shares similarities with pseudohyponatremia, which is the result of interference in the measurement of sodium levels in the context of indirect ion-selective electrode (ISE) methods. Both of these conditions can lead to falsely low measurements of the respective analytes.
Regarding the impact on other values in the chemistry panel such as blood urea nitrogen (BUN), creatinine (SCr), and calcium, these are usually measured differently in laboratories, and thus are not affected by the same mechanism that causes pseudohyponatremia or pseudohypobicarbonatemia. BUN and SCr are commonly measured using enzymatic or kinetic methods (e.g., Jaffe reaction for creatinine), while calcium is often measured using colorimetric methods, atomic absorption spectroscopy, or direct ISE. Because these analytes are measured by different methodologies, they are less likely to be influenced by the same factors causing pseudohyponatremia or pseudohypobicarbonatemia.
AJKDBlog: Let’s move to spurious potassium disorders. Before we jump into pseudo-diseases, can you explain to our learners the difference between a serum potassium level from a basic chemistry panel versus a whole blood potassium and how these differ?
Whole blood potassium refers to the concentration of potassium ions in the unseparated blood, and usually measured using a blood gas analyzer in hospital settings. Serum potassium is the acellular fraction of blood obtained after blood has been allowed to clot and the clot has been removed. This measurement is the most common method for assessing potassium levels. Plasma potassium is the acellular fraction of blood treated with an anticoagulant to prevent clotting. Typically, the serum potassium level is ~0.4 mmol/L higher than the plasma or whole blood levels because potassium is released during clot formation. The potential for pseudohyperkalemia comes from the significant difference in the extracellular (~4mmol/L) and intracellular (~150mmol/L) potassium concentrations that exists. Due to this difference, even a small release of potassium from blood cells into the plasma or serum fraction after sampling can greatly impact the measured potassium levels.
AJKDBlog: Now that we understand the basics, let’s discuss pseudohyperkalemia, another relatively common phenomenon in patients with leukemia or thrombocytosis. What are the factors related to collection, transport, and timing that lead to these falsely elevated levels and what can clinicians do to get more accurate values?
The factors related to blood collection, transport, and timing that can lead to pseudohyperkalemia include common causes like hemolysis (e.g., vigorous mixing), prolonged tourniquet time, delayed sample processing, and temperature, which are more pronounced in the presence of hematological malignancies. Serum samples can be particularly elevated in patients with elevated platelet counts > 500×109/L. Plasma potassium values result in more accurate values, but there are rare exceptions to this as well, as in the cases of reverse pseudohyperkalemia typically seen in patients with CLL. Whole blood with careful transport (<10 min) of the specimen to the laboratory can be done when cases of reverse pseudohyperkalemia are suspected. Ultimately, in the setting of malignancy, repeat and simultaneous testing should be encouraged when there is a suspicion of pseudohyperkaelmia.
AJKDBlog: Let’s now talk about spuriously decreased anion gaps. I would venture that we use the anion gap 99% of the time when talking about metabolic acidosis and whether the AG is high. Can you discuss some reasons where the serum AG is truly low and why patients with cancer might present with a falsely decreased AG?
A truly low anion gap can result from several factors, including hypoalbuminemia, hypercalcemia, hypermagnesemia, and lithium therapy. There are some rare circumstances where drugs that contain bromide ions interfere with the measurement of chloride ions, leading to a falsely low anion gap calculation. These factors are not unique to cancer patients, but can be seen more commonly, particularly hypoalbuminemia and hypercalcemia. In patients with cancer, a falsely decreased anion gap might be observed due to factors such as paraproteinemias, which can produce large amounts of positively charged monoclonal proteins. It is also worth noting that negatively charged monoclonal protein (IgA) can increase the anion gap.
AJKDBlog: Lastly, let’s talk about pseudo-levels of phosphorus, which is not a phenomenon I was familiar with before reading the article. It seems that the laboratory reasons for this are quite different from the pseudohyponatremias. Please give us a brief overview of how phos levels may be falsely low or high.
Factitious levels of phosphorus can be affected by the laboratory analysis and co-administration of agents that can sequester phosphorus in vitro. For example, pseudo-hypophosphatemia can from intravenous administration of glucose or insulin, which may not reflect the patient’s true phosphorus status. There can also be in vitro release of phosphate when there is hemolysis. The methodology for measuring phosphorus is important to understanding how factitious levels can occur. Inorganic phosphate forms an ammonium phosphomolybdate complex in the presence of sulfuric acid, and this concentration is directly proportional to phosphate concentration and is measured photometrically. Paraproteins exert interference usually resulting in factitious hyperphosphatemia. but occasionally in hypophosphatemia. Deproteination can correct this artifact, therefore clinicians should have a suspicion of this phenomenon in the appropriate clinical setting.
Title: Spurious Electrolyte and Acid-Base Disorders in the Patient With Cancer: A Review
Authors: Raad Chowdhury, Anna-Eve Turcotte, Helbert Rondon-Berrios, and Biruh T. Workeneh