Hyperkalemia

Case 15-1: Might This Patient Have Pseudohyperkalemia?

A 5-year-old male had neurosurgery to remove a tumor in the frontal lobe of his brain. There were no complications during surgery, and his course while in the intensive care unit was uneventful. At the time of his transfer to the ward, his P _K was 4.0 mmol/L. The next morning, however, his P _K was 6.0 mmol/L. There was no hemolysis or any reason to suspect a laboratory problem in the measurement of the P _K . In addition, hyperkalemia was present in repeated blood testing. He was not given any medications that might cause a shift of K ⁺ ions out of cells, and his intake of K ⁺ ions was low. He did not have a family history of hyperkalemia. His ECG did not show signs of hyperkalemia. The concentration of K ⁺ ions in his urine (U _K ) was only 10 mmol/L, and he was not polyuric. A clinical decision was made to treat him with mineralocorticoids. Several days later, his P _K returned to the normal range. The suspicion of hypoaldosteronism was thought to be confirmed as the concentration of aldosterone in his plasma (P _Aldosterone ), when results became available several days later, was found to be very low.

Case 15-2: Hyperkalemia in a Patient Treated With Trimethoprim

A 23-year-old man had a long history of acquired human immunodeficiency syndrome. He now developed pneumonia due to Pneumocystis jiroveci . His dietary intake has been poor and he appeared malnourished. On admission, he was febrile, his effective arterial blood volume (EABV) did not seem to be contracted, and the electrolyte values in his plasma were all in the normal range. Three days after receiving treatment with sulfamethoxazole and trimethoprim, his blood pressure was low, his pulse rate was high, and his jugular venous pressure was low. Of note, his P _K was 6.8 mmol/L. His ECG showed tall, peaked T waves. His laboratory data in plasma and urine samples that were obtained on that day are summarized in the following table. His urine volume was 0.8 L/day.

Case 15-3: Chronic Hyperkalemia in a Patient With Type 2 Diabetes Mellitus

A 50-year-old male with a 5-year history of type 2 diabetes mellitus was referred for investigations of hyperkalemia. His P _K ranged from 5.5 to 6 mmol/L in a number of measurements that were done over the last several weeks. He was on an angiotensin converting enzyme (ACE) inhibitor for treatment of hypertension, but hyperkalemia persisted after this medication was discontinued. He was noted to have microalbuminuria, but no other history of macrovascular or microvascular disease related to diabetes mellitus. He is currently on amlodipine 10 mg once a day. On physical examination, his blood pressure was 160/90 mm Hg, his jugular venous pressure was about 2 cm above the level of the sternal angle, and he had pitting edema around his ankles. Results of laboratory investigations are shown in the following table:

Hormones That Affect the Distribution of K ⁺ Ions Between the ECF and ICF Compartments

Effect of Metabolic Acidosis on the Distribution of K ⁺ Ions Between the ECF and the ICF Compartments

Transport of monocarboxylic acids (e.g., ketoacids or L-lactic acid) into cells on the monocarboxylic acid transporter (MCT) is an electroneutral process and hence it does not have a direct effect on a transcellular shift of K ⁺ ions. Nevertheless, entry of organic acids into cells may have an indirect effect that promotes the shift of K ⁺ ions into cells. In more detail, when L-lactic acid produced during vigorous exercise, for example, enter nonexercising cells (e.g., hepatocytes) on the MCT, the release of H ⁺ ions inside the cells may create a high local concentration of H ⁺ ions at the inner aspect of the cell membrane in the vicinity of NHE-1, which may activate NHE-1 and increase the electroneutral entry of Na ⁺ ions into these cells. The export of Na ⁺ ions by the Na-K-ATPase causes a more negative voltage in cells and thereby the retention of K ⁺ ions in cells.

Conversely, acids that cannot enter cells via the MCT (e.g., HCl, citric acid) may cause a shift of K ⁺ ions out of cells, resulting in hyperkalemia (see Chapter 13 , Figure 13-7 ).

Hyperkalemia in Patients With Tissue Catabolism

Hyperkalemia may be seen in patients with a crush injury or tumor lysis syndrome. In these patients, factors that compromise the renal excretion of K ⁺ ions are usually present as well. In patients with DKA, there is a total body deficit of K ⁺ ions because both K ⁺ ions and phosphate anions, released from cells in this catabolic state, are lost in the urine. Despite this deficit of K ⁺ ions, hyperkalemia is commonly present as a result of a shift of K ⁺ ions out of cells secondary to lack of actions of insulin. The corollary is that during therapy for DKA, complete replacement of the deficit of K ⁺ ions must wait for the provision of intracellular constituents (e.g., phosphate, essential amino acids, magnesium) and the presence of anabolic signals.

Hypertonicity and Shift of K ⁺ Ions out of Cells

A rise in effective osmolality (i.e., tonicity) in the interstitial fluid causes the movement of water out of cells via aquaporin-1 (AQP1) water channels in cell membranes. This raises the concentration of K ⁺ ions in the ICF, which provides a chemical driving force for the movement of K ⁺ ions out of cells. Although some may call this osmotic drag, this is not the correct description of this process, because the movement of K ⁺ ions out of cells is not through AQP1 but through specific K ⁺ ion channels (see Chapter 13 , Figure 13-8 ).

K ⁺ Ion Secretion in the CDN

The process of secretion of K ⁺ ions by principal cells in the CDN has two elements. First, a lumen-negative transepithelial voltage must be generated by the electrogenic reabsorption of Na ⁺ ions (i.e., reabsorption of Na ⁺ ions without their accompanying anions, which are largely Cl ⁻ ions) via the epithelial sodium ion channel (ENaC) in the luminal membrane of principal cells in the CDN. Second, the presence of a sufficient number of open renal outer medullary K ⁺ ion channels (ROMK) in the luminal membrane of principal cells.

Aldosterone actions lead to an increase in the number of open ENaC units in the luminal membrane of principal cells in the CDN and hence the rate of electrogenic reabsorption of Na ⁺ ions. Aldosterone binds to its receptor in the cytoplasm of principal cells and the hormone–receptor complex enters the nucleus, leading to the synthesis of new proteins, including the serum and glucocorticoid regulated kinase-1 (SGK-1). SGK-1 increases the number of open ENaC in the apical membrane of principal cells via its effect to phosphorylate and inactivate the ubiquitin ligase, Nedd 4-2 (see Chapter 13 , Figure 13-9 ).

An electroneutral NaCl transport process in CDN seems to be mediated by the parallel activity of the Na ⁺ ion-independent Cl ⁻ / ${{\text{HCO}}_3}^{-}$ anion exchanger (called pendrin) and the Na ⁺ ion-dependent Cl ⁻ / ${{\text{HCO}}_3}^{-}$ anion exchanger (NDCBE) (see Chapter 13 , Fig. 13-10 ). Increased electroneutral NaCl reabsorption diminishes the luminal-negative voltage and hence the rate of secretion of K ⁺ ions. An increase in the concentration of ${{\text{HCO}}_3}^{-}$ ions and/or an alkaline luminal fluid pH seem to increase the amount of K ⁺ ions secreted in the CDN. An increase in the concentration of ${{\text{HCO}}_3}^{-}$ ions in the fluid in the lumen of the CDN may inhibit pendrin and hence NDCBE and the electroneutral NaCl reabsorption. This may result in an increased rate of electrogenic reabsorption of Na ⁺ ions and a higher negative-lumen voltage in CDN. In addition, an increase in the luminal fluid ${{\text{HCO}}_3}^{-}$ concentration may increase the abundance and activity of ENaC in the luminal membrane of principal cells in CDN.

A complex network of “With No Lysine” (WNK) kinases, WNK4 and WNK1, through effects on the Na ⁺ /Cl ⁻ ion cotransporter (NCC) in the DCT and ROMK in the CDN, may function as a switch to change the aldosterone response of the kidney to either conserve Na ⁺ ions or excrete K ⁺ ions.

WNK4 is thought to inhibit NCC activity by reducing its abundance in luminal membranes by diverting post-Golgi NCC to the lysosome for degradation. Angiotensin II (ANG _II ) signaling through its AT1 receptor converts WNK4 from an NCC-inhibiting to an NCC-activating kinase. The activated form of WNK4 phosphorylates members of the STE-20 family of serine/threonine kinases, specifically SPAK and OSR1. Phosphorylated SPAK/OSR1 in turn phosphorylate and activate NCC. Alternative promoter usage of the WNK1 gene produces a kidney-specific, truncated form of WNK1, called KS-WNK1, and a more ubiquitous long form, called L-WNK1. L-WNK1 upregulates NCC either by blocking the inhibitory form of WNK4 or directly by phosphorylation of SPAK/OSR1. An increase in the rate of reabsorption of NaCl in the DCT decreases its delivery to the CDN. Therefore, the rate of electrogenic reabsorption of Na ⁺ ions in CDN is decreased and the negative-lumen voltage is diminished.

In addition to control by the lumen-negative voltage, the process for secretion of K ⁺ ions in principal cells is dependent on having a sufficient number of open ROMK channels in the luminal membrane of principal cells. Regulation of these channels is via phosphorylation/dephosphorylation-induced endocytosis/exocytosis, which involves a complicated mixture of kinases and phosphatases, including WNK kinases, tyrosine kinases, and SGK-1. L-WNK1 inhibits ROMK by inducing its endocytosis; the KS-WNK1 isoform inhibits this effect of L-WNK1. An increase in dietary intake of K ⁺ ions leads to an increased ratio of KS-WNK1 to L-WNK1, so there is reduced endocytosis of ROMK and increased rate of secretion of K ⁺ ions, if a large enough negative-lumen voltage can be generated. On the other hand, this ratio is decreased by dietary K ⁺ ion restriction, which leads to greater endocytosis of ROMK and hence less secretion of K ⁺ ions.

Flow Rate in the Terminal CDN

When vasopressin acts, the CDN becomes permeable to water because of the insertion of AQP2 water channels in the luminal membrane of its principal cells. The osmolality of fluid in the terminal CDN becomes equal to the plasma osmolality and therefore is relatively fixed. Therefore, the flow rate in the terminal CDN (i.e., the number of liters that exit the CDN) is determined by the number of effective osmoles present in the luminal fluid. These osmoles are largely urea, and Na ⁺ and K ⁺ ions with their accompanying anions. Because of the process of intrarenal urea recycling, most of the osmoles delivered to the terminal CDN are urea osmoles. In subjects eating a typical Western diet, the amount of urea that recycles would be approximately 600 mmol per day. This process of urea recycling adds an extra 2 L to the flow rate in the terminal CCD (600 mosmol divided by a luminal fluid osmolality that is equal to plasma osmolality, i.e., ∼300 mosmol/kg H ₂ O).