Hyperkalemia in Clinical Practice, an Important Reminder of Testing Modality

ABSTRACT

We describe a patient with hyperkalemia and ECG changes with persistent mild hyperkalemia without ECG changes following treatment. Their hyperkalemia was confounded by the presence of true hyperkalemia due to an acute kidney injury and pseudohyperkalemia due to significant thrombocytosis. This was corroborated by a difference in serum and plasma potassium testing.

1. Introduction

Frequently, hyperkalemia can be seen as an artifact in blood testing. Termed pseudohyperkalemia, this includes hemolysis during or after sample collection as well as cellular potassium release due to clotting in vitro. Hemolysis is a common cause of elevated serum potassium. Hemolysis results in elevated potassium, lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) [1]. Many laboratories report a hemolysis index based on the quantity of free hemoglobin [2]. Elevated hemolysis index may suggest a falsely elevated potassium, though this is not infallible. in vitro hemolysis can occur due to prolonged tourniquet use, excessive or vigorous handling, prolonged storage, delays to centrifugation as well as excessive centrifugation, and exposure to extremes of temperature, particularly cold temperatures [3, 4]. Excessive hand‐clenching at the time of venepuncture can result in release of potassium from muscle without hemolysis [5]. Patients with elevated cell counts due to myeloproliferative disorders or hematological malignancy can show an artefactual elevation in serum potassium on blood testing. This occurs where platelets release potassium during activation or where excessive white cells release potassium due to intrinsic fragility due to pathology, cell lysis due to metabolite depletion, or mechanical stress [6, 7]. Thus, inappropriate pre‐analytical sample handling can provide spurious results which may potentially lead to inappropriate patient treatment.

High platelet and white cell counts in myeloproliferative disorders can also result in falsely elevated potassium measurements due to the release of potassium during clotting [8]. In acute acidaemia, hydrogen ions are buffered intracellularly, resulting in potassium efflux to maintain electroneutrality [9]. States of hyperglycaemia and insulin deficiency can also lead to hyperkalemia [10]. Acutely or chronically impaired renal function can result in reduced elimination of potassium [11, 12]. Drugs commonly implicated in hyperkalemia include the renin‐angiotensin‐aldosterone‐system inhibitors, potassium‐sparing diuretics, non‐steroidal anti‐inflammatory drugs, digoxin, and trimethoprim.

Severe hyperkalemia can manifest with cardiac conduction abnormalities and arrhythmias. Other extracardiac manifestations include muscle weakness which may progress to paralysis. Characteristic electrocardiogram (ECG) findings include the development of tall and peaked T‐waves, PR prolongation and a short QT interval. With severe hyperkalemia, bradyarrhythmia, QRS widening, ventricular fibrillation and asystole may result [13]. Typically, a more rapid onset of hyperkalemia is associated with manifestation of typical signs and symptoms of hyperkalemia, whereas chronic hyperkalemia may not show characteristic ECG changes due to adaptation [13, 14]. The mechanism of these electrocardiographic changes is increased cellular potassium efflux leading to a less negative cardiomyocyte resting membrane potential and accelerated repolarization [14]. Management of hyperkalemia involves obtaining vital signs, ECG, repeating blood tests and identifying the underlying cause. If characteristic ECG features are present or repeat blood testing shows hyperkalemia, intravenous (IV) calcium, IV insulin and glucose are used to stabilize the myocardium and reduce extracellular potassium. Following treatment of the underlying cause, oral potassium binders such as sodium polystyrene sulfonate can be used to reduce absorption of potassium from the gastrointestinal tract. Patiromer is a new oral potassium binder PBS‐approved in Australia for patients with CKD stage 3–4 and persistent hyperkalemia. Another gut potassium‐binding agent, sodium zirconium cyclosilicate is currently undergoing regulatory approval in Australia.

2. Case History

A 78‐year‐old man is brought into a regional hospital from his residential aged care facility (RACF) following a fall. His past medical history was relevant for Parkinson's disease, polycythaemia rubra vera, chronic kidney disease stage 3b due to previous hypertension, valvular heart disease with bovine aortic valve replacement, complete heart block requiring pacemaker insertion and resected urothelial carcinoma. Polycythaemia rubra vera had been quiescent, having not required venesection in over two years prior to admission and he was not on any suppressive medication.

They were transferred to a tertiary receiving hospital. Initial blood testing via CHEM8⁺ & CG4⁺ (i‐STAT, Abbott) gas demonstrated a pH of 7.31 and potassium of 6.2 mmol/L. Due to concerns about this sample being haemolysed, the chemistry was repeated, demonstrating a potassium of 6.4 mmol/L. Formal blood analysis demonstrated a potassium of 7.0 mmol/L. There was no indication of in vitro or in vivo hemolysis. ECG demonstrated peaked T‐waves in chest leads new relative to previous ECGs. Other investigations demonstrated an acute‐on‐chronic kidney injury with eGFR 18 (baseline eGFR 38–42). Routine hematology testing demonstrated hemoglobin of 152 g/L, white cells of 16.9 × 10⁹, platelets of 533 × 10⁹ and hematocrit of 0.51. Physical observations including blood pressure, temperature, respiratory rate, oxygen saturation and pulse rate were within normal limits. Blood glucose was normal.

3. Methods/Treatment/Investigations

All blood testing was performed as follows. Routine biochemistry was performed after collection by hospital phlebotomy staff with blood collected by venepuncture into serum separator tubes (SST Vacutainer, Becton Dickinson). Blood was allowed to clot for at least 30 min and then centrifuged at 1000 × g for 10 min. Serum was then analyzed with the Atellica laboratory analyzer system (Siemens). All blood gas analysis was performed following venepuncture into a lithium heparin gas syringe and analyzed immediately after collection on the RAPIDpoint 500e Blood Gas System, Siemens in order to minimize artefactual potassium elevation.

The patients hyperkalemia was treated with 10 mL calcium gluconate 2.2 mmol/L and 5 units insulin (Actrapid) in 50 mL of 50% glucose. This caused an improvement in serum potassium to 5.4 mmol/L as measured by venous blood gas with lithium heparin anticoagulant (RAPIDpoint 500e Blood Gas System, Siemens), and resolution of the ECG changes. They were commenced on oral sodium polystyrene sulfonate 15 g twice a day. Medications were interrogated and no agents known to cause hyperkalemia were found.

During the admission, it was noted that despite resolution of the pre‐renal acute kidney injury with intravenous fluid resuscitation and mild acidaemia, low‐grade hyperkalemia (5.5–6.1 mmol/L) persisted on routine biochemical testing along with persistently elevated white cell count (14–17 × 10⁹) and platelets (630–694 × 10⁹) (Table 1). Despite this, there were no ECG changes suggestive of hyperkalemia. On these occasions, the treating team re‐checked the potassium with venous blood gas analysis with lithium heparin anticoagulant analyzed immediately on the RAPIDpoint 500e Blood Gas System, Siemens, which returned results within the normal range. Further workup revealed a trans‐tubular potassium gradient (TTKG) of 8 and serum aldosterone‐renin ratio of 2.0. On day 11 of admission, simultaneous testing revealed a potassium of 4.4 mmol/L on venous blood gas (RAPIDpoint 500e Blood Gas System, Siemens) and 5.3 mmol/L on standard biochemistry (Atellica, Siemens) indicating a 0.9 mmol/L difference between the two testing modalities.

TABLE 1.

White cell count, platelet count and potassium concentration in serum or plasma during hospital stay.

Day of admission	Day 1 (presentation)				Day 2			Day 3	Day 4	Day 5	Day 6	Day 7	Day 8		Day 10		Day 11
Time	14:40	15:20	19:16	22:17	01:38	08:16	13:38	08:15	07:58	08:39	08:47	08:21	08:13	16:05	07:56	11:43	07:30
Sample appearance	Clear		Clear			Clear		Clear	Haem 1+	Clear	Clear	Clear	Clear		Clear		Clear
White cell count (×109)	16.9		15.5			14.8		15.2	14.6	14.0	15.0	13.5	13.6		17.1		14.9
Platelet count (×109)	533		523			501		529	567	574	627	627	627		694		641
Serum potassium concentration (mmol/L)	7.0		6.8			6.1		5.4	5.1	4.8	5.5	5.7	6.1		6.0		5.3
Plasma potassium concentration via venous blood gas (mmol/L)				5.2 (after insulin)	4.9		4.8							4.8		4.7	4.4
Plasma potassium concentration via iSTAT device (mmol/L)	6.2	6.4
Difference	0.8																0.9
Electrocardiograph changes (if any)	Peaked T‐waves		Peaked T‐waves			Normal ECG		Normal ECG					Normal ECG		Normal ECG
Phase of illness	Acute kidney injury							Acute kidney injury recovery				Baseline renal function (creatinine)
	True hyperkalemia plus pseudohyperkalemia				Pseudohyperkalemia

4. Discussion

The observation of elevated platelet counts resulting in elevated potassium levels was first described by Hartmann and Mellinkoff [15]. Subsequent research by Hartmann et al. looked at a cohort of six patients with myeloproliferative disorders and hyperkalemia. Their experimentation demonstrated hyperkalemia in serum attributable to elevated platelets as evidenced by lower potassium levels in platelet‐free plasma [16]. The authors used the term ‘spurious hyperkalemia’ to describe this phenomenon. Commonly, routine biochemical testing examines the serum, obtained after clotting whole blood. In practice, collected blood is allowed to clot, often in a serum separator tube (SST), prior to centrifugation to yield serum. The activation of platelets during the clotting cascade results in release of potassium from platelet degranulation, the effect of which is magnified in significant thrombocytosis [16, 17, 18].

Graber et al. analyzed patients with reactive thrombocytosis and developed regression modeling to elucidate a likely predicted serum potassium according to platelet count [19]. Nijsten et al. performed similar analysis, developing a regression model for the difference between serum and plasma potassium in patients with elevated platelets [20]. Similarly, a 2016 study by Roccaforte et al. examined 42 patients with varying platelet counts and found increasing platelet counts correlated strongly with increasing serum potassium but not plasma potassium levels [21]. Our testing confirmed a discrepancy between point‐of‐care assay and serum analysis of 0.9 mmol/L, similar to that obtained by Nijsten et al. and Roccaforte et al. [20, 21].

There have been other case reports demonstrating similar phenomena in patients with other causes of thrombocytosis. Pseudohyperkalemia was reported in a post‐splenectomy patient with platelets of 914 × 10⁹ and 2 mmol/L difference in serum and plasma potassium levels [22]. Similar findings were noted in a patient with essential thrombocytosis and platelets of over 1,000 × 10⁹ who had a 1.55 mmol/L difference in serum and plasma potassium concentration [23]. Another case describes a patient with diabetic ketoacidosis and apparent treatment‐resistant hyperkalemia which was determined to have pseudohyperkalemia due to a platelet count of 2,071 × 10⁹ [24]. In addition to elevated platelet counts, the concept of pseudohyperkalemia occurring due to elevated white cell counts in chronic lymphocytic leukemia is well‐documented in the literature [7, 25, 26].

Pre‐analytical factors are an important consideration in the evaluation of hyperkalemia. The finding of hyperkalemia should always be considered within the context of other blood testing, which can provide clues in the case of hemolysis or pseudohyperkalemia due to elevated cell counts. In patients with myeloproliferative disorders and elevated white cells or platelets, testing blood samples to obtain plasma potassium concentration via point‐of‐care test or blood gas analyzer will provide results indicative of the true level of potassium. Alternatively, heparinized blood collection tubes can be used which prevent the release of intracellular potassium during coagulation [8].

Although our local hospital and health service protocol supports calcium use in this setting, international recommendations vary and often reserve calcium administration for more severe ECG changes.

This case illustrates the diagnostic complexity when genuine and pseudo‐hyperkalemia coexist, and underscores the importance of integrating clinical, electrocardiographic, and laboratory data to avoid therapeutic errors.

5. Conclusion

In the case we describe, the patient was considered to have likely two concomitant pathologies resulting in an overlay of true hyperkalemia and pseudohyperkalemia. These were an acute kidney injury superimposed on chronic kidney disease with mild acidosis as well as pseudohyperkalemia due to elevated platelet counts from polycythaemia rubra vera. In this case, the measured trans‐tubular potassium gradient (TTKG) of 8 is considered appropriate for the degree of hyperkalemia and would argue against hypoaldosteronism [27, 28]. Similarly, a normal aldosterone‐renin ratio also argues against hypo‐aldosteronism as a cause for hyperkalemia. Following resolution of the component of hyperkalemia attributable to acute kidney injury, a persistent low‐grade hyperkalemia was seen. Corroborating the ongoing hyperkalemia being artefactual is the fact that there were ECG changes consistent with hyperkalemia on presentation which were not present later during admission, coupled with the measured 0.9 mmol/L difference between the two testing modalities and persistently elevated platelet counts (Table 1). Whilst the use of tandem alternative blood testing methods is not routinely used, its use in the cases of patients with myeloproliferative disorders and significant leukocytosis or thrombocytosis may provide an opportunity to provide more accurate results.

In summary, pseudohyperkalemia can arise in patients with profoundly elevated platelet or white cell counts and typically should not have ECG features of hyperkalemia. Where there is clinical suspicion of high white cell or platelet count as the cause for pseudohyperkalemia, utilize plasma or blood gas testing where available. Appropriate recognition of pseudohyperkalemia in clinical practice is important to avoid inappropriate treatment which could potentially lead to patient harm. Misinterpretation of pseudohyperkalemia may result in unnecessary administration of potassium‐lowering therapies, including insulin, or ion‐exchange resins, which may be harmful in certain patient populations.

Author Contributions

Andrew G. Turner: conceptualization, investigation, methodology, writing – original draft, writing – review and editing. Deepak L. Vardesh: conceptualization, formal analysis, investigation, supervision, writing – review and editing.

Consent

Signed patient consent was obtained from the patients next of kin for the publication of deidentified information relevant to the case.

Conflicts of Interest

The authors declare no conflicts of interest.

Turner A. G. and Vardesh D. L., “Hyperkalemia in Clinical Practice, an Important Reminder of Testing Modality,” Clinical Case Reports 13, no. 10 (2025): e71242, 10.1002/ccr3.71242.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.