Dr. Sanela REDZEPAGIC

Renal Advanced trainee, RPAH/Concord hosp.

Feb 2012

1. Physiology of Potassium metabolism and potassium distribution

2. Renal potassium handling with normal renal function and CKD

3. Potassium shifts

4. Hypokalaemia clinical picture

5. Diagnostic investigation

6. Treatment

Potassium ◦ essential for many cellular functions

◦ present in most foods

◦ excreted primarily by the kidney

“Western diet “ K content~approx.70 -150 mmol

The gastrointestinal tract efficiently absorbs potassium, and dietary potassium intake varies greatly with the composition of the diet.

Potassium absorption from the GIT major intracellular cation only about 2% of total body K extracell. K is a major determinant of intracellular Osmolality. Most intracellular K is contained within muscle cells.

◦ Total body K is roughly proportional to lean body mass. ◦ An average 70-kg adult has about 3000 to 3500 mmol.

The ratio between ICF and ECF K concentrations strongly influences cell membrane polarization, which in turn influences important cell processes, such as the conduction of nerve impulses and muscle (including myocardial) cell contraction.

Even small alterations in serum K concentration can have

significant clinical manifestations.

This asymmetric potassium distribution between ICF and ECF compartments strongly depends upon the effects of the electrogenic sodium pump, Na+,K+-ATPase that achieves by active uptake, which occurs in virtually all cells. ◦ Na+,K+-ATPase transports two potassium ions into cells in

exchange for extrusion of three sodium ions high intracellular potassium &low intracellular sodium activity

Long-term potassium homeostasis is accomplished primarily through changes in renal potassium excretion via collecting duct potassium transport. Serum potassium is filtered efficiently by the glomerulus.

Potassium reabsorption, which decreases renal potassium excretion, occurs through the action of the active potassium-reabsorbing transporter H+,K+ ATPase.

Normal maintenance of this ratio and membrane potential is critical for normal nerve conduction and muscle contraction.

The major factors regulating H+,K+-ATPase expression and activity are:

1. Potassium balance • Potassium depletion increases H+,K+-ATPase expression

• increased active potassium reabsorption and decreased potassium excretion.

2. Aldosterone increases H+,K+-ATPase expression and activity decreasing net potassium excretion, serve as a “counterbalancing factor” to minimize the hypokalaemia that results generally from increased aldosterone.

3. Acid-base status

Metabolic acidosis has both direct and indirect (mediated through alterations of ammonia metabolism) effects that increase H+,K+-ATPase potassium transport. In some cases, this may contribute to the hyperkalemia that can occur with metabolic acidosis.

Aldosterone lowers serum potassium concentration by two major mechanisms. ◦ stimulates potassium movement into cells (redistribution),

and ◦ increases potassium excretion in the kidney and, to a lesser

extent, in the gut.

The primary renal action of aldosterone is to stimulate sodium reabsorption; but with ample sodium delivery to the late distal nephron and collecting duct, this promotes enhanced flow-dependent potassium excretion.

Aldosterone has many effects that increase principal cell potassium secretion. These include increases in Na+,K+-ATPase expression and increased apical expression of the sodium channel ENaC. The net effect is increased potassium secretion.

The proximal tubule reabsorbs the majority (~65% to 70%) of filtered potassium. Very little regulation occurs in response to changes in dietary potassium intake.

Potassium is secreted by the descending loop of Henle, at least in deep nephrons, and is reabsorbed by the ascending loop of Henle through the action of the Na+-K+-2Cl− cotransporter (Fig. 9.5A). This results in modest net potassium reabsorption in the loop of Henle.

This absorption can be reversed to secretion, however, by administration of a loop diuretic or by substantial potassium loading. Nevertheless, the majority of potassium excretion is regulated normally through active secretion and absorption in the distal tubule and collecting duct.

Collecting duct potassium transport occurs through distinct cell types that allow fine control of renal potassium excretion.

The principal cell of the cortical collecting duct secretes potassium (Fig. 9.5B). Sodium reabsorption through the apical sodium channel (ENaC) stimulates basolateral Na+,K+-ATPase, and the active turnover of this pump maintains high intracellular potassium concentrations.

Subsequent to basolateral potassium uptake, potassium is secreted into the luminal fluid by apical potassium channels and KCl cotransporters. Intercalated cells reabsorb potassium through an apical H+,K+-ATPase (Fig. 9.5C).This protein actively secretes H+ into the luminal fluid in exchange for potassium, resulting in potassium reabsorption.

The presence of two separate potassium transport processes, secretion by principal cells and reabsorption by intercalated cells, enables effective regulation of renal potassium excretion.

Potassium homeostasis is relatively well preserved until glomerular filtration rate (GFR) is reduced substantially.

Patients with chronic kidney disease (CKD) have more difficulty handling an acute potassium load. ◦ decreased nephron number

Patients with CKD are also routinely treated with medications that alter renal potassium handling, decrease renal potassium sensitivity and result in higher serum potassium concentrations. ◦ ACE inhibitors ◦ ARBs ◦ β-adrenergic receptor blockers.

Insulin moves K into cells via effect on the Na+,K+-ATPase pump through a mechanism separate from its stimulation of glucose entry. ◦ High concentrations of insulin lower serum K ◦ Low concentrations of insulin (in DKA) cause K to move out

of cells, thus raising serum K, sometimes even in the presence of total body K deficiency.

β-Adrenergic agonists, especially selective β2-agonists, move K into cells - β2-Adrenergic receptor activation increases intracellular cyclic adenosine monophosphate production, which stimulates Na+,K+-ATPase–mediated potassium uptake.

Whereas β-blockade and α-agonists promote movement of K out of cells.

Acute metabolic acidosis causes K to move out of cells, whereas acute metabolic alkalosis causes K to move into cells.

However, changes in serum HCO3 concentration may be more important than changes in pH; acidosis caused by accumulation of mineral acids (nonanion gap, hyperchloremic acidosis) is more likely to elevate serum K.

In contrast, metabolic acidosis due to accumulation of organic acids (increased anion gap acidosis) is not associated with hyperkalemia. Thus, the hyperkalemia common in diabetic ketoacidosis results more from insulin deficiency than from acidosis.

Acute respiratory acidosis and alkalosis affect serum K concentration less than metabolic acidosis and alkalosis. Nonetheless, serum K concentration should always be interpreted in the context of the serum pH (and HCO3 concentration).

Hyperosmolality, if it is due to effective osmoles, can induce potassium shifts out of cells and result in hyperkalemia.

The proposed mechanism is that increased plasma osmolality induces water movement out of the cells, which decreases cell volume and increases intracellular potassium concentrations. This is then thought to result in feedback inhibition of Na+,K+-ATPase, shifting potassium from the intracellular to the extracellular compartment and normalizing intracellular potassium concentration.

Both glucose, in a patient with intact insulin secretion, and urea are ineffective osmoles because they rapidly cross plasma membranes and therefore do not alter cell volume.

Importantly, hyperglycemia in a nondiabetic patient, if it stimulates endogenous insulin secretion or if exogenous insulin is given, can cause insulin-induced cellular potassium uptake and resultant hypokalemia.

Exercise hyperkalemia due to α-adrenergic receptor activation that shifts potassium out of the skeletal muscle cells.

hyperkalaemia induces arterial dilation, which increases skeletal muscle blood flow and acts as an adaptive mechanism during exercise.

In patients with pre-existing potassium depletion, post-exercise hypokalemia may be severe and rhabdomyolysis may occur.

Hypokalemia (serum K < 3.5 mmol/L)

routine serum electrolyte measurement. ◦ deficit in total body K stores

◦ abnormal movement of K into cells.

Hypokalemia is a common clinical problem!

The cause of which can usually be determined from the history (as with diuretic use, vomiting, or diarrhoea). ◦ In some cases, however, the diagnosis is not readily

apparent.

Serum K measurement

ECG

Detailed history to search for a cause

Symptoms and Signs Mild hypokalemia (serum K 3 to 3.5 mmol/L)

rarely causes symptoms. Serum K < 3 mmol/L ◦ muscle weakness ◦ may lead to paralysis and respiratory failure. ◦ Cardiac hyperexcitability may occur with severe

hypokalemia.

Other muscular dysfunction includes ◦ cramping, fasciculations, paralytic ileus, hypoventilation,

hypotension, tetany, and rhabdomyolysis.

Persistent hypokalemia can impair renal concentrating ability, causing polyuria with secondary polydipsia.

Cardiovascular ◦ Hypokalemia has been shown experimentally to increase

blood pressure modestly (5 to 10 mm Hg), and similarly, potassium supplementation can lower blood pressure.

◦ Potassium deficiency probably increases blood pressure by stimulating sodium retention, with resultant intravascular volume expansion, and by sensitizing the vasculature to endogenous vasoconstrictors.

◦ In part, sodium retention is related to decreased expression of the kidney-specific isoform of WNK1, which leads to increased NCC- and ENaC-mediated sodium reabsorption in the distal convoluted tubule and cortical collecting duct, respectively.

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Cardiac effects of hypokalemia are usually minimal until serum K concentrations are < 3 mmol/L.

Hypokalaemia ◦ sagging of the ST segment

◦ depression of the T wave

◦ elevation of the U wave.

◦ the T wave becomes progressively smaller, a flat or positive T wave merges with a positive U wave, which may be confused with QT prolongation

premature ventricular and atrial contractions

ventricular and atrial tachyarrhythmias,

2nd- or 3rd-degree atrioventricular block.

ventricular fibrillation may occur.

Patients with significant pre-existing heart disease and patients receiving digoxin are at risk of cardiac conduction abnormalities even from mild hypokalemia.

Hormonal ◦ Hypokalemia impairs insulin release and also

induces insulin resistance, resulting in worsened glucose control in diabetic patients.

◦ Insulin resistance observed with thiazide diuretics may be due to endothelial dysfunction mediated by thiazide-induced hypokalemia and hyperuricemia.

Renal ◦ Hypokalemia leads to:

reduced medullary blood flow

increased renal vascular resistance that may predispose to hypertension

tubulointerstitial and cystic changes

alterations in acid-base balance

impairment of renal concentrating mechanisms.

• Tubulointerstitial and Cystic Changes

◦ tubulointerstitial fibrosis that is generally greatest in the outer medulla.

◦ Reversible, it may result in renal failure.

◦ Renal hypertrophy and predisposes to renal cyst formation, particularly when there is increased mineralocorticoid activity.

Acid-Base ◦ Metabolic alkalosis is a common acid-base

consequence of potassium depletion and is due to increased renal net acid excretion.

◦ Conversely, metabolic alkalosis may increase renal potassium excretion, resulting in potassium depletion.

◦ Severe hypokalemia can lead to respiratory muscle weakness and the development of respiratory acidosis.

Polyuria ◦ Severe hypokalemia also impairs concentrating

ability, causing mild polyuria, typically 2 to 3 liters per day. Both increased thirst and mild nephrogenic diabetes insipidus contribute to the polyuria.

◦ Hepatic Encephalopathy

◦ Hypokalemia increases renal ammonia production, approximately half of which returns to the systemic circulation through the renal veins and may worsen hepatic encephalopathy

When the mechanism not evident clinically ◦ 24-h urinary K excretion

◦ Urinary potassium: creatinine ratio

◦ serum Mg concentration

◦ Acid- base status - ABG

Hypokalemia results typically from one of four causes: ◦ 1.pseudohypokalemia – artificial/ phlebotomy

◦ 2.redistribution

◦ 3. extrarenal potassium loss

◦ 4. renal potassium loss.

◦ 5. medication related

Skin -excessive sweating GI tract potassium losses: ◦ Chronic diarrhoea, including chronic laxative abuse and

bowel diversion

◦ Clay (bentonite) ingestion, which binds K and greatly decreases absorption

◦ Vomiting

◦ Protracted gastric suction (which removes volume and HCl, causing the kidneys to excrete HCO3 and, to electrically balance lost HCO3, K)

◦ Rarely, villous adenoma of the colon, which causes massive K secretion

◦ GI K losses may be compounded by concomitant renal K losses due to metabolic alkalosis and stimulation of aldosterone due to volume depletion.

Redistribution --Intracellular shift of potassium: The transcellular shift of K into cells may also cause hypokalemia. Glycogenesis during TPN or enteral hyperalimentation

(stimulating insulin release) After administration of insulin Stimulation of the sympathetic nervous system, particularly with

β2-agonists (eg ventolin, terbutaline etc), which may increase cellular K uptake

Thyrotoxicosis (occasionally) due to excessive β-sympathetic stimulation (hypokalemic thyrotoxic periodic paralysis)

Familial periodic paralysis , a rare autosomal dominant disorder characterized by transient episodes of profound hypokalemia thought to be due to sudden abnormal shifts of K into cells. Episodes frequently involve varying degrees of paralysis. They are typically precipitated by a large carbohydrate meal or strenuous exercise.

Renal losses ◦ Excess mineralocorticoid effect can directly increase

K secretion by the distal nephrons and occurs in any of the following:

◦ Adrenal steroid excess that is due to Cushing's syndrome, primary hyperaldosteronism, rare renin-secreting tumors, glucocorticoid-remediable aldosteronism (a rare inherited disorder involving abnormal aldosterone metabolism), and congenital adrenal hyperplasia.

Medication:

Diuretics are by far the most commonly used drugs that cause hypokalemia. K-wasting diuretics that block Na reabsorption proximal to the distal nephron include ◦ Thiazides

◦ Loop diuretics

◦ Osmotic diuretics

Laxatives - By inducing diarrhoea, especially when abused, can cause hypokalemia.

Surreptitious diuretic or laxative abuse ◦ Among patients preoccupied with weight loss and

among health care practitioners with access to prescription drugs.

Other drugs that can cause hypokalemia include ◦ Amphotericin B

◦ Antipseudomonal penicillins (eg, carbenicillin)

◦ Penicillin in high doses

◦ Theophylline intoxication ( both acute and chronic)

Magnesium deficiency inhibits renal potassium retention. ◦ diuretic-induced hypokalemia and in certain cases

of aminoglycoside- and cisplatin-induced potassium wasting.

Bicarbonaturia can result from: ◦ metabolic alkalosis

◦ distal renal tubular acidosis

◦ treatment of proximal renal tubular acidosis.

In each case, the increased distal tubular bicarbonate delivery increases potassium secretion.

Rarely, genetic defects lead to excessive aldosterone production. In glucocorticoid-remediable aldosteronism, an adrenocorticotropic

hormone (ACTH)−regulated promoter is linked to the gene for aldosterone synthase, the rate-limiting enzyme for aldosterone synthesis. As a result, aldosterone synthase expression is regulated by ACTH, and hyperaldosteronism ensues.

congenital adrenal hyperplasia, there is persistent adrenal synthesis of 11-deoxycorticosterone, a potent mineralocorticoid. This condition can be recognized by the associated effects on sex steroid production.

In another rare condition, glucocorticoid hormones activate the mineralocorticoid receptor.

Some compounds, such as glycyrrhetinic acid, found in some chewing tobacco and licorice preparations, inhibit 11β-HSD, allowing cortisol to exert mineralocorticoid-like effects.

In severe Cushing's syndrome, circulating cortisol exceeds the metabolic capacity of 11β-HSDH and can cause hypokalemia.

Bartter syndrome results from genetic abnormalities in proteins involved in thick ascending limb of the loop of Henle sodium and potassium transport. They typically present at a young age with severe volume depletion and growth retardation. ◦ Hypokalemia ◦ reduced or normal blood pressure ◦ hyper-reninemia, ◦ metabolic alkalosis ◦ hypercalciuria.

Gitelman's syndrome genetic abnormalities in the proteins involved in distal convoluted tubule sodium and potassium transport and causes clinical abnormalities similar to those seen with excessive thiazide diuretic use. ◦ similar to Bartter syndrome, except that patients have milder clinical manifestations than

and usually are diagnosed later in life. ◦ Hypocalciuria ◦ Hypokalaemia

Liddle syndrome - mutation resulting in activation of the collecting duct epithelial sodium channel ◦ excessive sodium reabsorption ◦ potassium excretion ◦ volume expansion ◦ Hypertension ◦ Hypokalaemia ◦ suppressed renin and aldosterone levels.

The body responds to chronic hypokalemia due to potassium losses by shifting potassium from the intracellular to the extracellular space.

The risks associated with hypokalemia must be balanced against the risks of therapy.

Usually, the primary short-term risks are cardiovascular arrhythmias and neuromuscular symptoms.

The clearest indications for urgent treatment: ◦ Hypokalemic periodic paralysis, ◦ Severe hypokalemia in a patient requiring urgent surgery ◦ Acute myocardial infarction in the patient with significant

ventricular ectopy.

In such cases, KCl can be given intravenously at a dose of 5 to 10 mmol during 15 to 20 minutes.

If more rapid replacement is necessary, 20 mmol/h can be administered through a central venous catheter, but simultaneous continuous ECG monitoring should be used under these circumstances.

There are two major components to the diagnostic evaluation: ◦ assessment of urinary potassium excretion to

distinguish renal potassium losses (eg, diuretic therapy, primary aldosteronism) from other causes of hypokalemia

◦ assessment of acid-base status

some causes of hypokalemia are associated with metabolic alkalosis or metabolic acidosis.

A 24-hour urine collection is the most accurate method to measure urinary potassium excretion.

A normal individual can, in the presence of potassium depletion that is not due to urinary losses, lower urinary potassium excretion below 25 to 30 mmol per day on a 24-hour urine collection.

Higher values suggest urinary potassium wasting.

The minimum urine potassium concentration that can be achieved with hypokalemia is 5 to 15 mmol/L.

Some have suggested that extrarenal losses are present if the urine potassium concentration is less than 15 meq/L, while substantially higher values suggest at least a component of potassium wasting.

Urine potassium-to-creatinine ratio ◦ less than 13 meq/g creatinine (1.5 meq/mmol

creatinine) in hypokalaemia due to:

poor dietary intake

transcellular potassium shifts

gastrointestinal losses

previous use of diuretics.

The following diagnostic possibilities should be considered in the patient with hypokalemia of uncertain origin:

Metabolic acidosis + low urinary potassium excretion

◦ suggestive of lower gastrointestinal losses due to laxative abuse or a villous adenoma.

Metabolic acidosis + urinary potassium wasting ◦ diabetic ketoacidosis ◦ type 1 (distal) ◦ type 2 (proximal) renal tubular acidosis.

Metabolic alkalosis + low urinary potassium excretion ◦ surreptitious vomiting (often in bulimic patients in an attempt to

lose weight) or diuretic use if the urine collection is obtained after the diuretic effect has worn off.

◦ some patients with laxative abuse present with metabolic alkalosis, rather than the expected metabolic acidosis

Metabolic alkalosis + urinary potassium wasting + normal blood pressure ◦ diuretic use ◦ Vomiting ◦ Gitelman or Bartter syndrome.

Urine chloride concentration is often helpful, ◦ normal (equal to intake) in Gitelman or Bartter syndrome ◦ high or low with diuretics depending upon whether or not the

diuretic is still acting ◦ low in vomiting

Urine pH, which should be above 7.0 if significant bicarbonaturia is present.

Metabolic alkalosis + urinary potassium wasting + hypertension ◦ suggestive of surreptitious diuretic therapy in a patient with

underlying hypertension, renovascular disease, or one of the causes of primary mineralocorticoid excess.