Specific Causes of Hypokalemia

A summary of the causes of hypokalemia is provided in Table 4 and Figure 11. We shall comment only briefly on some of these disorders, either because they are common or because new strides have been made in understanding their pathophysiology.

Gitelman Liddle And Bartter Syndrome

• Mg malabsorption syndrome

• Drugs: e.g., cisplatin, • Gitelman's aminoglycosides syndrome

• Mg malabsorption syndrome

• Drugs: e.g., cisplatin, • Gitelman's aminoglycosides syndrome

Figure 10. Differential diagnosis of hereditary causes of hypokalemia. The initial step is to rule out common causes of hypokalemia which may be denied by the patient. Here the urine electrolytes become very important (Table 1). A finding of persistent excretion of Na+ and Cl- despite a contracted ECF volume narrows the differential diagnosis to causes where there is obvious basis for hypomagnesemia or not. Finding Mg2+-poor urine will suggest a low intake or poor GI absorption of Mg2+. Failure to find an obvious cause for renal Mg2+ wasting suggests that Bartter's or Gitelman's syndrome may be present. Reproduced with permission [104].

Disorders with Hypokalemia and a Low ECF Volume

Diuretic-induced Hypokalemia

- Underlying pathophysiology: Two factors contribute to the development of hypokalemia in patients receiving diuretics: a high rate of flow in CCD and an increased net secretion of K+ due to the effect of aldosterone (released in response to a low ECF volume).

- Clinical features: Hypokalemia is usually modest in degree. A fall in plasma [K+]

to < 3 mM is observed in < 10% of patients, usually within the first 2 weeks of therapy [58].

- Diagnosis requirement: One must ask if the patient has been taking diuretics. At times, abuse of diuretics may be denied, so screening the urine for diuretics may be needed (choose a urine when diuretics are acting, i.e. one which contains appreciable Na+ and Cl-).

- Differential diagnosis: If diuretic abuse is firmly denied by the patient, a diagnosis of Bartter's or Gitelman's syndrome may be suspected because the urine will

Table 4. Causes of Hypokalemia

I. Decreased intake of K+

II. Shift of K+ into cells

- Hormones: Insulin, sympathomimetics

- Gain of anions in the intracellular fluid (recovery phase of ketoacidosis, refeeding after cachexia, treatment of pernicious anemia)

- Metabolic alkalosis

- Others: Hypokalemic periodic paralysis.

III. Intestinal loss of K+

- Diarrhea, ileus

IV. Excessive loss of K+ in urine

1. High flow CCD, e.g. diuretics, genetic disorders with inhibition of Na+-trans-port (Bartter's syndrome or Gitelman's syndrome).

A) Disorders leading to a relatively "faster Na+" in the CCD

- High aldosterone, high renin: Low effective circulating volume (diuretics, vomiting, diarrhea), malignant hypertension, renal artery stenosis, renin-secreting tumor

- High aldosterone, low renin: Adrenal adenoma or bilateral adrenal hyperplasia, glucocorticoid remediable aldosteronism

- Low aldosterone, low renin: Decreased 11-PHSDH activity (apparent mineralocorti-coid excess syndrome), inhibition of 11-PHSDH (e.g. licorice, carbenoxolone, swallowed chewing tobacco), very high levels of glucocorticoids (e.g. ACTH-pro-ducing tumor), increased activity of ENaC (Liddle's syndrome, drugs: amphotericin B)

B) Disorders leading to a relatively "slower Of in the CCD

- Bicarbonaturia: Vomiting, use of acetazolamide, distal RTA, patients with proximal RTA treated with alkali.

- Hypomagnesemia.

often contain abundant Na+ and Cl- in both settings. Diuretic abuse should be suspected if even one spot urine has little Na+ and Cl- reflecting the normal renal response to low ECF volume (Table 1). This diagnosis can be confirmed by screening a urine sample with abundant

Na+ and Cl- for diuretics. The urine electrolytes also provide clues to the differential diagnosis in patients with hypokale-mia due to diuretic abuse from those with hypokalemia due to occult vomiting or the abuse of laxatives. In the occult vo-miter, the key finding is a very low urine [Cl-] (Table 1). In the laxative abuser with a contracted ECF volume, the urine [Na+] will be low, but the urine [Cl-] may be high if there is a high rate of excretion of NH4+ in response to the hyperchlore-mic metabolic acidosis (Table 1).

- Molecular basis: None.

- Therapy: Some of the issues discussed here under treatment of diuretic-induced hypokalemia will apply to the treatment of other settings with hypokalemia. Specific issues related to therapy of diuretic-induced hypokalemia will also be addressed.

Whether a mild degree of hypokalemia should be treated is debatable. Since patients with ischemic heart disease, those with left ventricular hypertrophy, and those treated with digitalis may be at increased risk for arrhythmias, even a mild degree of hypokalemia should be avoided in these patients. While it is generally stated that a fall in plasma [K+] from 4 to 3 mM indicates a total body deficit of 200 - 400 mmol of K+ and may be as much as 800 mmol if plasma [K+] falls to 2 mM [59]; this is not a useful quantitation in any individual patient. Factors that may induce a shift of K+ into the ICF compartment may also be present, and it is not possible to determine the magnitude of the total body deficit of K+ based on the value of plasma [K+]. The bottom line is that careful monitoring of plasma [K+] is required as the K+ deficit is being repleted. Two other issues bear mentioning. First, with chronic hy-

Acetazolamide Hypokalemia

Figure 11. Approach to the patient with hypokalemia. The causes for excessive excretion of K+ (> 15 - 20 mmol/day) despite hypokalemia are too high a flow rate in the CCD (left limb) and/or too high a [K+] in the lumen of the CCD (right limb). Both flow rate and [K+]ccd should be evaluated in each patient. Final considerations are shown by the bullet symbols. A slower Cl- reabsorption in the CCD is suggested by high plasma renin activity and NaCl wasting despite low ECF volume; the converse applies for faster Na+ reabsorption. Reproduced with permission [104]. Abbreviations: CAI = Carbonic anhydrase inhibitor type of diuretic, AME = Apparent mineralocorticoid excess, GRA = Glucocorticoid-remedial aldosteronism.

Figure 11. Approach to the patient with hypokalemia. The causes for excessive excretion of K+ (> 15 - 20 mmol/day) despite hypokalemia are too high a flow rate in the CCD (left limb) and/or too high a [K+] in the lumen of the CCD (right limb). Both flow rate and [K+]ccd should be evaluated in each patient. Final considerations are shown by the bullet symbols. A slower Cl- reabsorption in the CCD is suggested by high plasma renin activity and NaCl wasting despite low ECF volume; the converse applies for faster Na+ reabsorption. Reproduced with permission [104]. Abbreviations: CAI = Carbonic anhydrase inhibitor type of diuretic, AME = Apparent mineralocorticoid excess, GRA = Glucocorticoid-remedial aldosteronism.

pokalemia, the CCD may become hypo-responsive to the kaliuretic effect of al-dosterone and thus there is a risk for the development of hyperkalemia during K+ replacement [60, 61]. Second, patients who have disorders, or are taking drugs that may impair their ability to shift K+ into cells or to excrete K+ in the urine, may be particularly at risk of developing hyperkalemia with therapy.

In the absence of conditions that may limit the oral intake of K+ or its absorption by the gut (e.g. vomiting, ileus or the absence of bowel sounds), the oral route is usually preferred. At times, however, the urgency of treatment may necessitate using the IV route. When using a peripheral vein, the [K+] in the infusate should not exceed 40 mM, as higher

[K+] may irritate small veins and cause painful phlebitis. In general, the rate of K+ administration should not exceed 60 mmol/hour.

Since patients with diuretic-induced hy-pokalemia have both K+ and Cl- deficits, K+ should be given as its Cl- salt. In general, tablets are better tolerated than the liquid form. Most tablets are slow-release preparations, either microencapsulated or in wax matrix, which have occasionally caused ulcera-tive or stenotic gastrointestinal lesions. A salt substitute may be an inexpensive and generally well-tolerated form of K+ supplementation (Co-salt provides 14 mmol of K+ per gram). Contrary to customary belief, increasing intake of K+-rich food (e.g. bananas) is not an effective way to replace a K+ deficit. Bananas provide little K+, only about 1 mmol per inch.

Some particular issues about hypokalemia and diuretic use are worth highlighting. First, because the risk of development of hypoka-lemia is dose-dependent and because increasing the dose of hydrochlorothiazide beyond 12.5-25 mg does not usually result in further benefit in terms of blood pressure control, the lowest effective dose of this drug should be used. Second, the degree of renal wasting of K+ can be minimized by restricting NaCl intake to 100 mmol/day. Third, the use of K+-sparing diuretics provides an effective way of reducing the renal loss of K+. The ENaC blockers (amiloride and triametrene) are generally better tolerated and lack the gastrointestinal and hormonal side effects (impotence, decreased libido, amenorrhea, gynecomastia) that may occur with the aldosterone competitive inhibitor spironolactone. The availability of combination tablets of hydrochlorothiazide with amiloride or triametrene also makes compliance less of an issue. These drugs, however, blunt the renal response to an increase in the plasma [K+] and also have a long half-life. Therefore they should be used cautiously in patients on P-blockers, angoitensin-converting enzyme (ACE) inhibitors, or non-steroidal anti-inflammatory drugs (NSAID) and those with an underlying renal disease.

Vomiting-induced Hypokalemia

- Underlying pathophysiology: Because the [K+] in gastric fluid is usually <15 mM, hypokalemia in patients with vomiting or nasogastric suction results primarily from the loss of K+ in the urine. Aldosterone is released in response to Ang II that is formed because of ECF volume contraction. Aldosterone leads to a more open ENaC in the CCD (Figure 5). Delivery of HCO3- to the lumen of CCD is the result of a transient rise in its concentration in plasma due to vomiting

(Figure 12). A higher distal delivery of HCO3- causes a higher net secretion of K+ (Figure 13 and [34, 37]). To a lesser extent, hypokalemia may be the result of a shift of K+ into the ICF compartment due to the alkalemia. Once the degree of hypokalemia becomes more severe, the rate of K+ excretion declines, but not to the very low rates in otherwise normal subjects consuming a low-K+ diet [50].

- Clinical features: Hallmarks are a significant degree of hypokalemia, metabolic alkalosis, and a very low [Cl-] in the urine (Table 1). In a patient with recent vomiting, the urine may contain an abundant Na+ despite ECF volume contraction because the excretion of HCO3- obligates the excretion of Na+.

- Diagnosis requirement: Key elements are a history of vomiting, a significant degree of hypokalemia, metabolic alka-losis, and a very low [Cl-] in the urine (Table 1). The use of urine electrolytes may help reveal the basis for hypokale-mia in a patient with occult vomiting.

- Differential diagnosis: If the patient denies vomiting, other causes of hypokale-mia with a low ECF volume must be considered (Table 4).

- Molecular basis: None.

- Therapy: Therapy is directed towards the underlying cause of vomiting and the administration of K+. Again, these patients also have a deficit of Cl-. K+ should be administered as its Cl- salt along with NaCl as needed.

Hypokalemia in Patients with Hyperchloremic Metabolic Acidosis

- Pathophysiology: The 2 major entities to consider in these patients are distal RTA due to a low rate of H+ secretion in the

And Hco3 Stomach
Figure 12. H+ Secretion in stomach and mass balance for H+. The structure on the left represents a parietal cell in the stomach. There is an net gain ofHCO3-anda loss of Cl-from the ECF compartment when HCl is secreted. Reproduced with permission [104] of the authors.
Licorice Hypokalemia

Figure 13. Aldosterone and the augmented reabsorption of NaCl. The adrenal gland is depicted by the triangular structure. The secretagogue on the left forthe release of aldosterone is angiotensin II. Angiotensin II, by stimulating the reabsorption of HCO3- in the proximal and distal convoluted tubules, diminishes the delivery of HCO3-to the CCD and thereby a kaliuresis is not promoted. The secretagogue on the right forthe release of aldosterone is K+. Hyperkalemia, by inhibiting the reabsorption of HCO3-in the proximal convoluted tubule, increases the delivery of HCO3- to the CCD and thereby a kaliuresis is promoted. Reproduced with permission [104].

Figure 13. Aldosterone and the augmented reabsorption of NaCl. The adrenal gland is depicted by the triangular structure. The secretagogue on the left forthe release of aldosterone is angiotensin II. Angiotensin II, by stimulating the reabsorption of HCO3- in the proximal and distal convoluted tubules, diminishes the delivery of HCO3-to the CCD and thereby a kaliuresis is not promoted. The secretagogue on the right forthe release of aldosterone is K+. Hyperkalemia, by inhibiting the reabsorption of HCO3-in the proximal convoluted tubule, increases the delivery of HCO3- to the CCD and thereby a kaliuresis is promoted. Reproduced with permission [104].

distal nephron and loss of NaHCO3 via the gastrointestinal (GI) tract. For the former, the key element in the pathophysiology of their hypokalemia is the retention of HCO3- in the lumen of the CCD.

In the latter, loss of K+-rich colonic fluids (especially from distal colon) can lead directly to hypokalemia. In some cases of diarrhea, however, the degree of hypokalemia is modest. The reason is that al though the presence of aldosterone (due to ECF volume contraction) causes the ENaC in the CCD to be open, limited delivery of HCO3- to the CCD (low filtered HCO3- due to metabolic acidosis plus the effects of Ang II, metabolic acidosis, and hypokalemia to enhance proximal reabsorption of HCO3- [37]) leads to electroneutral reabsorption of Na+ in the CCD. Therefore, aldosterone acts as an NaCl-retaining rather than a kaliuretic hormone (Figure 13).

- Clinical picture: Hypokalemia with hy-perchloremic metabolic acidosis.

- Diagnosis requirement: In patients with distal RTA due to a low rate of H+ secretion in the distal nephron, there is a low rate of NH4+ excretion and a relatively high urine pH (about 6.5) (see chapter I-3 on Acid-base Balance for more details). In patients with a GI problem, a history of a diarrheal illness may be obtained. Abuse of laxatives, however, may be firmly denied. If suspected, measurement of the urine electrolytes may provide helpful clues. The urine [Na+] will be low if the ECF volume is contracted, but the [Cl-] in the urine is characteristically high reflecting the high rate of NH4+ excretion in response to metabolic acidosis (Table 1). At times, one might have to rely on measurements of stool electrolytes and other evidence for laxatives in the stool to confirm the diagnosis.

- Differential diagnosis: Other causes of hypokalemia with a low ECF volume are illustrated in Table 4.

- Molecular basis: Usually this is not an issue.

- Therapy: Because these patients have hy-pokalemia and metabolic acidosis, K+ can be given with HCO3- or other anions that can be metabolized to HCO3- (e.g. citrate). Nevertheless, because the admi nistration of HCO3- may cause the shift of K+ into the ICF compartment, K+ should be replaced for the most part as its Cl- salt early in therapy.

Bartter's and Gitelman's Syndromes

- Pathophysiology: The pathophysiology of Bartter's syndrome can be thought of as having a loop diuretic acting 24 hours a day. The pathophysiology of Gitel-man's syndrome can be thought of as having a thiazide diuretic acting 24 hours a day.

The high rate of K+ excretion in both disorders has 2 components: a high flow rate in CCD and a high [K+] in the lumen of the CCD. The high flow rate in the CCD is due to the very large delivery of Na+ and Cl-, the result of their inhibited reabsorption in upstream nephron segments (Figure 3). The high [K+] in the lumen of the CCD is due to a relatively faster rate of reabsorption of Na+ relative to that of Cl-. The rate of Na+ reabsorption is stimulated because of the contraction of the ECF volume, one of the hallmarks of the clinical picture. Hypoma-gnesemia may contribute to the patho-physiology of renal K+ wasting, especially in patients with Gitelman's syndrome [62].

- Clinical picture: These uncommon disorders are characterized by ECF volume contraction due to renal salt wasting, hy-pokalemia, and metabolic alkalosis (Table 4). Hypomagnesemia is more consistently seen in patients with Gitelman's syndrome. While hypercalciuria is found in many patients with Bartter's syndrome, an extreme degree of hypocalciuria

Hypercalciuria Furosemide

Figure 14. Possible lesions for Bartter's syndromes. A stylized nephron is shown on the left with the thick ascending limb of the loop of Henle (LOH) shown by the dashed oval. The structure to the right represents an enlargement of the thick ascending limb of the LOH. The possible lesions are the Na+-K+-2 Cl- cotransporter (site 1), the luminal K+ channel (site 2), occupation of the basolateral Ca2+ receptor by a cationic ligand (site 3), or the Cl- channel in the basolateral membrane (site 4).

Figure 14. Possible lesions for Bartter's syndromes. A stylized nephron is shown on the left with the thick ascending limb of the loop of Henle (LOH) shown by the dashed oval. The structure to the right represents an enlargement of the thick ascending limb of the LOH. The possible lesions are the Na+-K+-2 Cl- cotransporter (site 1), the luminal K+ channel (site 2), occupation of the basolateral Ca2+ receptor by a cationic ligand (site 3), or the Cl- channel in the basolateral membrane (site 4).

is a characteristic finding in almost all patients with Gitelman's syndrome [62]. In contrast to patients with Bartter's syndrome, patients with Gitelman's syndrome should have the ability to elaborate a maximally concentrated urine when ADH acts, unless there is another lesion that caused renal medullary damage as chronic hypokalemia or the chronic use of drugs that might damage this area of the kidney such as NSAIDs.

- Diagnosis requirement: The presence of hypokalemia with renal salt wasting and persistently elevated [Na+] and [Cl ] in the urine is the hallmark of the diagnosis (Table 1).

- Differential diagnosis: The major differential diagnosis is with patients with diuretic abuse, laxative abuse, or occult vomiting. The use of urine electrolytes in this differential diagnosis is a critical step (Table 1).

- Molecular basis: Patients with Bartter's syndrome seem to represent a heterogeneous group with regard to the molecular lesions (Table 3, Figure 14). Mutations that cause a loss of function have been identified in the genes encoding for the bumetonide-sensitive Na+-K+-2 Cl co-transporter [63], the luminal K+ channel (ROM-K) [64], and the Cl- channel in the basolateral membrane of the thick ascending limb of the loop of Henle [65]. Those patients with a ROM-K channel defect may have their initial presentation as hy-perkalemia and NaCl wasting because ROM-K is the major K+ channel in principal cells of the CCD. The biochemical findings evolve to the more typical ones of hypokalemia and metabolic alkalosis with time.

The vast majority of patients with Gitelman's syndrome have mutations in the gene encoding the NaCl co-transporter in the early distal convoluted tubule [66]. Nevertheless, some patients have all the clinical characteristics of Gitelman's syndrome without a recognized mutation in this transporter [67].

- Therapy: Correction of hypokalemia is extremely difficult in these patients, even with large supplements of K+. Hypoma-gnesemia seems to be an important factor in the enhanced kaliuresis in some, but not all patients with Gitelman's syndrome. Correction of hypomagnesemia with oral magnesium is usually limited by gastrointestinal side effects. K+-sparing diuretics may help conserve K+ but they may also exacerbate renal salt wasting. ACE inhibitors have been tried in some patients with variable success, but hypotension is a major concern with this therapy. We are concerned about the prolonged use of NSAIDs because of the potential for chronic renal dysfunction.

Hypokalemia Due to Cationic Drugs Like Gentamicin

- Pathophysiology: Gentamicin is an antibiotic that has the capacity to bind to a receptor for Ca2+ on the basolateral aspect of cells of the thick ascending limb of the loop of Henle (Figure 14) [68]. This binding of gentamicin leads to inhibition of the luminal K+ channel (ROM-K), and thereby to furosemide-like effects. Therefore, the pathophysiology of gentamicin-induced hypokalemia can be thought of as having a loop diuretic acting 24 hours a day. The high rate of excretion of K+ has 2 components: a high flow rate in the CCD and a high [K+] in the lumen of the CCD. The high [K+] in the lumen of the CCD is due to a faster rate of Na+ reabsorption relative to that of Cl-. Hypomagnesemia may contribute to the pathophysiology of renal K+ wasting in these patients. A similar story might apply for other drugs that bind to the Ca2+ receptor in the loop of Henle such as cisplatin.

- Clinical picture: This disorder is characterized by ECF volume contraction due to renal salt wasting, polyuria, a fall in the glomerular filtration rate (GFR), hypoka-lemia, hypomagnesemia, hypercalciuria, and metabolic alkalosis.

- Diagnosis requirement: The presence of the features outlined above in a patient receiving gentamicin or drugs with a similar effect.

- Differential diagnosis: All the conditions described above must be considered.

- Molecular basis: None.

- Therapy: Discontinue the drug. Wait for its side effects to wear off, but this may take a considerable amount of time. Supportive therapy with Na+, K+, and Mg2+ should be given if the patient is symptomatic and in danger from these deficits.

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  • Sofia
    How thiazides cause hypokalemia?
    5 years ago

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